Mutagenesis Advance Access originally published online on December 8, 2006
Mutagenesis 2007 22(1):15-33; doi:10.1093/mutage/gel055
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A review of genome mutation and Alzheimer's disease
1 CSIRO Health Sciences and Nutrition, PO Box 10041 Adelaide BC, Adelaide, South Australia 5000, Australia 2 Discipline of Physiology, School of Molecular and Biomedical Sciences The University of Adelaide, Adelaide, South Australia 5000, Australia
Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder of the brain and is the commonest form of dementia. The prevalence of this disease is predicted to increase 3-fold over the next 30 years and to date no reliable and conclusive diagnostic test exists that will identify individuals presymptomatically of susceptibility risk. This review examines the molecular, genetic, dietary and environmental evidence underlying the known pathology of AD and proposes a biologically plausible chromosome instability model to explain some of the features of the disease. Genome damage biomarkers such as aneuploidy of chromosome 17 and 21, oxidative damage to DNA and telomere shortening together with abnormal expression of APP, ß amyloid and tau proteins are discussed in terms of their potential value as risk biomarkers. These biomarkers could then be used in diagnosis and the evaluation of potentially effective preventative measures.
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Introduction |
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Alois Alzheimer (Figure 1) was born in Marktbriet, Germany on June 14, 1864. He studied medicine at the Universities of Berlin, Tübingen, and Würzberg where he completed his doctoral thesis under the supervision of Albert Kölliker on ceruminal glands in 1887. From 1888 to 1903 Alzheimer worked as a medical resident and then later as a senior physician at the municipal mental asylum in Frankfurt. It was here that he forged his friendship with Franz Nissl, who developed histopathological stains that allowed the histology of nervous tissue from various neurodegenerative disorders to be studied.
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On November 25, 1901 a patient called Auguste D was admitted to Frankfurt hospital where she was seen and treated by Alzheimer. She exhibited various behavioural and psychiatric symptoms including paranoia, delusions, hallucinations and impaired memory (1
). After having suffered 5 years of illness she died in 1906. Her clinical notes and brain were forwarded onto Alzheimer in Munich, where over the next few months he examined Auguste's brain in great detail. At the 37th Conference of German psychiatrists meeting in Tübingen on November 4, 1906, Alzheimer reported for the first time the histopathological changes that he had witnessed in Auguste's brain. In his journal he wrote "in the centre of an almost normal cell there stands out one or several fibres due to their characteristic thickness and peculiar impregnability. Numerous small miliary foci are found in the superior layers. They are determined by the storage of a peculiar substance in the cerebral cortex. All in all we have to face a peculiar disease process" (2). The impregnable fibres so described by Alzheimer were the neurofibrillary tangles, whereas the miliary foci were to be later referred to as the amyloid based neuritic plaques. Both these structures initially described by Alzheimer are now recognized as the characteristic hallmarks of a disease that now bears his name. In 1910 Emil Kraepelin published the 8th edition of his book The Handbook of Psychiatry where he describes a particularly serious form of senile dementia with early age of onset as Alzheimer's disease.
Having worked with Kraepelin in Munich from 1903 to 1912, Alzheimer was appointed to the position of professor of Psychiatry in Breslau, Poland. However with the arrival of the First World War conditions became increasingly more difficult. He found himself under increasing stress until finally his health started to fail. Alois Alzheimer died in a uraemic coma as a result of rheumatic endocarditis on December 19, 1915 at the age of 51. Alzheimer's many years of dedicated research provided the foundation for today's extensive research programmes, into trying to understand a disease that is predicted to make a huge social and financial impact on the 21st Century. Alzheimer's disease (AD) has been classified as a progressive degenerative disorder of the brain and is the most common form of dementia, with between 50 and 70% of all clinically presented cases being histopathologically confirmed as AD at post mortem (3). Worldwide a new case of dementia is diagnosed every 7 s. The global incidence of dementia is estimated to be 24.3 million, with 
4.6 million new cases being diagnosed annually (4,5). Currently between 165 000 and 180 000 Australians suffer from this disease, with an annual cost in 2004 to the Australian government of $3.6 billion dollars in lost productivity and medical care (6,7). These numbers are set to increase 3-fold over the next 30 years as a greater proportion of an already ageing population reaches retirement age. Advancing age is the major contributing factor for increased risk of developing Alzheimer's. After the age of 65 a doubling of risk occurs every 5 years affecting 30% of individuals aged 
80 years (3,8,9) It is estimated that by 2025 at least 34 million people worldwide will suffer from AD (10).
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Clinical diagnosis |
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At present, based upon criteria of cognitive impairment and behavioural changes patients can be clinically diagnosed with an accuracy between 60 and 70% of having AD (11
). The most commonly used criteria are those outlined by the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and-related Disorders Association (NINCDS–AD & DA), published in 1984 (12). According to this document, criteria for probable diagnosis for Alzheimer's includes dementia as determined by the mini mental state examination (MMSE) (13), which allows a brief quantitative measure of cognition status to be determined. It can be used as a measure of cognitive decline, to document cognitive changes with the passage of time and in relation to treatment, and as an effective tool in screening for elements of cognitive impairment. Dementia is diagnosed when two of the following parameters are impaired: amnesia (progressive worsening of memory), aphasia (impairment of speech), apraxia (the inability to perform motor tasks) and agnosia (the inability to identify and recognise individuals or objects, despite having knowledge of the characteristics of those individuals and objects). Individual assessment includes various psychiatric and behavioural changes such as depression, misidentifications, delusions and hallucinations that invariably lead to an individual's inability to perform everyday tasks, resulting in some form of full-time care being required (8).
The age of onset for AD is usually after the age of 65 years but can be earlier if influenced by genetic mutations in familial Alzheimer genes. Other forms of systemic disorders, which could also account for the progressive decline in both memory and cognition function invariably need to be ruled out. Laboratory testing can aid in the identification of conditions that need to be diagnostically eliminated in order to achieve a more accurate diagnosis when a dementia profile is being evaluated. A complete blood cell count and urinalysis profile is necessary to exclude signs of anaemia and infection; metabolic disorders can be evaluated through analysis of serum metabolites (such as glucose, calcium, urea and creatinine), as well as, by performing various liver function tests to eliminate other certain metabolic disorders such as Wilson's syndrome or Laennec's cirrhosis. Additionally, neurosyphilis as well as micronutrient deficiencies in folate and B12 need to be excluded as they can simulate symptoms of dementia, thereby, making an accurate diagnosis more difficult to achieve (14).
Until recently there was no diagnostic test available that could reliably and conclusively identify those individuals for increased presymptomatic risk of AD. Consequently it was impossible to develop and implement effective preventative measures to curb the progress of the disease. However recently a simple non-invasive skin test that measures dilation of blood vessels has been developed, that reflects a decline in function in specific blood vessel cell types affected by the disease. It is claimed that different dementias can be differentiated and that detection can be made up to two years before conventional clinical diagnosis (15,16). A further technique has been developed that involves the use of an intravenous amyloidophilic compound labelled with 19F. This compound when administered to amyloid precursor protein (APP) transgenic mice, specifically labelled amyloid plaques that could be visualized in living subjects by magnetic resonance imaging (MRI). This technique would allow the identification of the disease at an earlier stage in presymptomatic individuals and to determine disease progression in response to various preventative measures and selected treatments (17).
Although the pathogenesis of the disease is still not completely understood, it has been shown that at post mortem there are two histopathological changes that occur within the brain. These changes involve the abnormal clustering of proteins, which characterize individuals with AD. This abnormal clustering occurs in two forms: (i) those that occur within the neurons, i.e. the neurofibrillary tangles and (ii) those that cluster extracellularly outside of the neuronal body, i.e. the amyloid based neuritic plaques (Figure 2). Early changes occur within the entorhinal cortex projecting into the hippocampus, which leads to disruption of learning and short-term memory processes. Further protein deposits have been found within the temporal, frontal and inferior parietal lobes mapping the spread of the disease throughout the brain. Later developments in the pathology of AD include neuronal cell death resulting in loss of tissue leading to overall shrinkage of brain size (10).
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Tau and neurofibrillary tangles |
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Neurofibrillary tangles are composed of the microtubule-associated protein tau, the gene of which is located at chromosome 17q21.1 (18
). The TAU gene comprises of 15 exons, with 11 of the exons coding for all of the major tau isoforms. Splicing of exons 2, 3 and 10 results in the six different forms of the tau protein. These forms differ from each other by the presence or absence of two N-terminal exons and a single C-terminal exon, which results in variation of their amino acid length, which ranges from 352 to 441 amino acids (19).
Tau proteins are important as they associate with tubulin in the formation of microtubules. Microtubules impart shape and structure to cells and generate cellular transport networks that allow movement of micronutrients, neurotransmitters and organelles that are essential for normal cellular function (20). The tau protein of neurofibrillary tangles consists of paired helical threads that are hyperphosphorylated. This hyperphosphorylation leads to a dissociation between tau and tubulin resulting in a breakdown in the brain transport network eventually leading to resistance to protein degradation (20), loss of biological activity and cell death (18,20).
The level of tau phosphorylation is probably determined by the regulation of protein kinases that modify tau through phosphorylation, and phosphatases that dephosphorylate the modified tau. Tau kinases such as GSK3, cdk5 and p38 are known as proline kinases and regulate proline modified serine and threonine motifs. Both Cyclic-AMP and Ca2+/cadmodulin dependent kinases together with protein kinase C are known as non-proline kinases that modify non-proline serine and threonine motifs. Sequences involved in binding tau to tubulin are coded for within the C-terminal exon and are positioned adjacent to the sequences for the tubulin binding repeats (21) (Figure 3).
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Tau phosphorylation is linked to microtubule stabilization by regulating the binding of tau to the microtubules. In AD under conditions following phosphorylation, decreased binding occurs leading to a breakdown in microtubule stability resulting in tau aggregation within the neurons (22
). Hyperphosphorylation may also lead to microtubule spindle defects, resulting in aneuploidy for a number of chromosomes including chromosome 17 that may lead to abnormal expression of Alzheimer's-related genes such as TAU.
In the neurodegenerative disorder frontotemporal dementia, the density of the neurofibrillary tangles is directly correlated with the severity of exhibited dementia (10,23). This disorder is the result of point mutations within exon 10 of the TAU gene such as Leu266Val and Glu342Val. The disorder is not associated with any amyloid peptide formation or plaque deposition (24,25). This is important as it suggests that dementia can arise directly from abnormal processing and accumulation of tau (26,27) that arises independently of any influence of abnormal amyloid metabolism.
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ß amyloid and neuritic plaques |
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The amyloid based neuritic plaque occurs extracellularly to the neuron body having originated within the neuron and been secreted as a soluble peptide. It is thought to be the first histopathological change to occur in AD (10
). The plaque consists primarily of the 42 amino acid ß amyloid peptide (Aß42) originating from the abnormal processing of APP, the gene of which is located on chromosome 21q21. APP is a cell-surface protein of 695–770 amino acids long, and plays a functional role in neurite outgrowth, cell adhesion, synaptic functions and the induction of apoptosis (28).
The protein runs through the membrane leaving a short intracellular terminal and a longer terminal extracellularly (Figure 4) .The ß amyloid peptide is normally snipped out of the APP protein that is adjacent to the cell membrane. APP proteolysis is mediated by a series of secretase enzymes 
, ß and 
(29,30). Under normal conditions, a harmless P3 fragment is formed by cleavage by and secretases resulting in a 40 amino acid ß peptide (28,31).
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The
secretase is thought to be made up of metalloproteases of the tumour necrosis factor -converting enzyme and a disintegrin matrix (32). ß Sectretase has been identified as the enzyme BACE (ß site APP cleaving enzyme) the gene of which is located on chromosome 11. The secretase is a complex multi protein comprising of four components, presenilin, nicastrin, Aph-1 and Pen2 all of which are required for effective proteolytic activity (33).
In the Alzheimer's brain, aberrant proteolysis occurs involving ß secretase which produces a series of products, that after having been cleaved by gamma secretase, gives rise to the Aß42 (29). Aberrant proteolysis results in an abnormal accumulation of soluble Aß42, which aggregates into oligomers. When fibrillized and subjected to an astrocyte induced inflammatory response it matures into an insoluble neuritic plaque measuring between 10 and 120 µm. (28,31,34).
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Intraneuronal Aß42 is generated initially within the endoplasmic reticulum, golgi body and endosomes of the neuron where it accumulates, eventually transferring to the extracellular space of the neuron as a soluble peptide (35
–38). It has also been shown to accumulate in those vulnerable areas of the brain that are sensitive to Alzheimer's-related pathological changes such as the perikaryon of the pyramidal neurons of the hippocampus and entorhinal cortex (39) (Figure 6). Intraneuronal Aß42 could be considered to be an early pathological biomarker of the disease and has been shown to be a contributory factor to neuronal dysfunction.
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Billings et al. (40
) have shown in a transgenic mouse model that animals manifested symptoms of cognitive impairment that correlated with intraneuronal Aß42 accumulation within the hippocampus and amygdala. The mice were free from both tangle and plaque pathology suggesting these structures contribute to further cognitive decline during the later stages of the disease. It may also be that they are incidental endpoint structures that are not directly responsible for the causative factors leading to the pathology of the disease. By clearing the intraneuronal Aß42 using immunotherapy, the observed cognitive deficits were attenuated when memory was assessed after measuring tasks that involve the hippocampus. This implies that the intraneuronal Aß42 has a role in the initiation of early stage cognitive impairment and neuronal dysfunction in AD (40).
It has been shown that application of Aß42 to cultured neurons is neurotoxic and can directly initiate apoptosis (41,42). The presence of ß amyloid elevates apoptotic vulnerability when cells are under conditions of increased oxidative stress, which occurs naturally in the ageing brain. ß amyloid induced oxidative stress results in the generation of reactive oxygen species that can damage various cellular components such as cell membrane proteins, mitochondrial DNA, lipids and cytoplasmic proteins. In the brains of Alzheimer's patients these components have been shown to exhibit elevated levels of oxidative damage (43,44). ß amyloid causes neurons to undergo apoptosis by sensitizing their membranes following lipid peroxidation. The normal ATPases associated with the membrane are impaired leading to membrane depolarization, and a disruption in glucose and glutamate transportation and ATP energy depletion. ß amyloid also modifies calcium flow across the membrane (45). Calcium is involved in mechanisms associated with memory and learning, as well as, neuronal survival. The ß amyloid peptide disrupts calcium regulatory pumps within the membrane and elevates calcium influx through voltage dependent channels, possibly as a result of induced oxidative stress leading in turn to neuronal cell death (46).
Further signs of apoptosis in Alzheimer's brains include elevated DNA fragmentation and ß amyloid induced caspase activation. Caspases are a family of cysteine proteases and are the principal effectors of apoptosis. In Alzheimer's brains caspase 3 has been shown to use APP as a substrate, producing a potent apoptotic promoting peptide called C31 (47). Other caspases such as caspases 8, 9 and 12 have been shown to contribute to neurodegeneration (48,49). Nakagara et al. (49) has shown that caspase 12 located in the endoplasmic reticulum (which regulates cellular responses to stresses such as high calcium and free radicals) induces apoptosis as a result of ß amyloid toxicity. It has been suggested that caspase activation occurs initially at the nerve synapses (50), leading to an overall loss of cerebral nerve terminals and interneuronal communication within the neuronal network. This gradual degeneration of terminals may correlate with the individual's level of cognitive impairment. As nerve cells slowly undergo further terminal loss with the passage of time, the dysfunctional neurons eventually die in those areas of the brain that are initially susceptible to ß amyloid toxicity.
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Amyloid cascade hypothesis: plaques or tangles? |
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One of the topics that has generated a great deal of interest within Alzheimer's research is the question of which of the histopathological landmarks, the neurofibrillary tangle or the neuritic plaque, appears first? Does one influence the development of the other or do they in fact develop independently via two separate pathways? The amyloid cascade theory was proposed to explain the aetiology and progression of the disease (51
–53) and indeed still forms the backbone of explanation for Alzheimer's development. However in recent years it has been found that certain observations cannot be explained by the hypothesis in its current form (54,55). The cascade theory currently states that elevated deposits of the Aß42 occur as a result of missense mutations or a failure of clearance mechanisms that invariably lead to the production of neuritic plaques. These plaques precede intracellular accumulation of tau and eventually result in neuronal cell death (52,53). The hypothesis also suggests that the plaques produce hyperphosphorylated tangles through the abnormal regulation of kinases and phosphatases as the disease progresses (56).
Various lines of evidence have come to light in support of the hypothesis. First, mutations both within the APP and presenilin genes (genes implicated in early-onset AD) result in elevated production and accumulation of the Aß42 (51,57,58). The Aß42 is more sensitive to fibrillization and therefore also more sensitive to neuritic plaque formation (51). Over-expression of the APP gene leads to elevated ß amyloid production resulting in the development of amyloid plaques. Down's syndrome patients possess three copies of chromosome 21, which codes for the APP gene and are therefore susceptible to excessive expression of APP and possibly generation of an excess of Aß42. An identical brain histopathology to Alzheimer's patients is apparent in Down's syndrome patients between the ages of 30 and 40 years (59–61) with large numbers of tangles appearing between the third and fifth decades of life. Second, mutations within exon 10 of the TAU gene give rise to frontotemporal dementia characterized by cognitive impairment but occurring in the absence of plaque formation (10,24,25). This implies that severe tau production and accumulation is sufficient to produce symptoms of dementia independently of amyloid plaques and has little influence on the initiation of amyloid plaque formation. Thus Alzheimer's tangles would appear to be produced after changes in the amyloid production rather than before (51). Transgenic mouse models have been useful in yielding etiological clues to both the progression and underlying mechanisms associated with disease. JNPL3 transgenic mice expressing altered tau when crossed with Tg2576 transgenic mice expressing altered APP showed no change in the number, age of development and morphology of the neuritic plaques produced. However an increase in tau positive tangles was more substantial within the limbic system indicating a role for APP or Aß42 in the formation of neurofibrillary tangles (62). This suggests that changes in the processing of the APP gene occur prior to tau alteration. Additional experiments involving crossing APP transgenic mice with apolipoprotein allele 4 (APOE4) deficient mice resulted in offspring with a decrease in the deposition of ß amyloid, indicating an interaction with the APOE4 gene and amyloid processing (63). Figure 5 outlines a modified version of the amyloid cascade hypothesis proposed by Hardy (52) and Hardy and Selkoe (56).
Although no other model trying to explain the natural history of AD has been put forward, the model in its current form has come under a certain amount of criticism. It has not been able to account for a number of observations that are important in the pathology of AD. One of the main criticisms is that there is only a weak correlation between plaque density and the degree of severity of dementia (64). Additionally, transgenic mice over-expressing the APP gene have been shown to exhibit little or no neurodegeneration (65). Further a small number of cases have been reported involving exon 9 mutations within the Presenilin 1 (PSEN1) gene involving Alzheimer's patients with spastic parapesis (66,67). This condition is unusual in that few amyloid plaques appear within the brains of affected individuals. Further evidence has indicated that the neurofibrillary tangles appear at least a decade prior to the formation of neuritic plaques (68,69). Various studies have shown that tangles were present in areas of the hippocampus and entorhinal cortex in all non-demented patients over 60 years of age, whereas cases that were up to 90 years old were found without plaques (70,71). In their monumental study investigating 2661 cases Braak and Braak (69) found neurofibrillary tangles were evident in the entorhinal cortex in up to 98% of brains examined, whereas only 70% had any evidence of neuritic plaque deposition (69). Further analysis showed that the initial phase of tangle development preceded plaque deposition by up to two decades (72).
The problem is therefore how to explain the substantial evidence supporting the amyloid peptide as a causative agent of Alzheimer's on the one hand, with the equally strong evidence implying that tangle formation precedes plaque deposition and therefore does not fit into the current cascade hypothesis model. It has been proposed that neurofibrillary tangles are an independent feature accumulating slowly with age within the medial temporal lobes. However under the influence of altered amyloid metabolism, which leads to plaque formation during the initial stages of Alzheimer's, there is an acceleration of tangle formation that spreads further to include the neocortex (70). It appears that tangles form normally with age independently of plaque formation. The density of tangles increases with age in an exponential fashion and without any amyloid influence appears to remain confined to the medial lobe (73). As tangle physiology involves synaptic and neuronal loss there would be a stronger correlation between tangle density and degree of severity of dementia. This would be facilitated as soon as tangle acceleration occurs as a result of plaque influence (70). It would appear that since its initial conception the cascade hypothesis has been supported through a whole body of work that has emerged from laboratories from around the world. Alternative models have not been proposed to explain deficiencies within the cascade hypothesis with the same degree of experimental support that is available for the current model. With the passage of time and with the emergence of new experimental data, the current hypothesis will be either reshaped to explain the pathogenesis of the disease or be replaced with an alternative model, which will have to explain all facets of aetiology and progression of the disease.
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Genetics of AD |
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Inheritance of known genes that predispose to AD accounts for only 5–10% of all clinically presented cases (10
,74). Familial AD (FAD) can be classified as either early-onset or late-onset. The genes implicated in early-onset forms of the disease, which occur below 65 years of age are the APP gene located on chromosome 21q21; PSEN1 located on chromosome 14q24.3 and PSEN2 on chromosome 1q31–q42 (23,74,75). Mutations within the APP occur around the processing sites of the APP molecule resulting in increased production of the ß amyloid peptide (76). Most cases containing APP mutations have an age of onset between mid 40's and 50's but can be modified by the presence of the APOE genotype (57). Mutations within the APP gene appear to be family specific and do not occur within the majority of sporadic Alzheimer's cases. Missense mutations within the PSEN1 gene account for 18–50% of the early-onset autosomal dominant forms of AD (77). Mutations within the PSEN1 lead to a particularly aggressive form of the disease having an age of onset between 30 and 50 years, which is not influenced by the APOE genotype. However a polymorphism found within intron 8 of the PSEN1 gene was found to be associated with the development of the late-onset form of the disease (77,78). To date over 75 mutations have been found within the PSEN1 gene in families worldwide that are associated with the early-onset form of the disease (31). All mutations within PSEN1 increase production of the Aß42 (57,58). Mutations within PSEN2 have a variable age of onset (40–80 years), appear not to be influenced by APOE and result in increased ß amyloid peptide production (57).
The gene for APOE is located on chromosome 19q13.2 and certain polymorphisms are associated with the late-onset form of AD (>65 years) (23,79). The E3 allele is considered normal and occurs in 74% of the population; the E2 and E4 allele are less common, occurring in 10 and 16% of the population, respectively (10,79). The APOE gene does not cause Alzheimer's but acts as a marker altering individual risk based on possession of allelic combinations of the APOE4 allele (80). The highest risk is associated with the E4/E4 genotype. It has been proposed by Corder et al. (80), that each copy of the APOE4 allele reduces the age of onset by 7–9 years. An average age of onset of 85 years is given for individuals with no E4 alleles, 75 years for one allele and 68 years for individuals with two copies of the E4 allele (23,80).
Whereas genetic alterations in the previously mentioned four genes (Figure 7) are generally accepted as being implicated in causing FAD, other studies highlighting the potential role of other genes have come to light.
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Alpha 2 macroglobulin functions as a protease inhibitor and has been found in neuritic plaques. The gene is on chromosome 12p13.3 and variants of the gene are associated with the late-onset form of the disease (81
,82).
Genetic linkage analysis has identified a potential AD gene at or near the insulin degrading enzyme gene found on chromosome 10q23-25 which is involved in the cellular processing of insulin. At the current time further genetic analysis is being undertaken to determine a thorough assessment of this potential locus (83,84).
The monoamine oxidase A gene serves to regulate the metabolism of neuroactive and vasoactive amines within the central nervous system. Polymorphisms within this gene have also been implicated in the pathology of AD (85).
Myeloperoxidase (MPO) is an enzyme present in circulating monocytes and neutrophils and is part of the host's polymorphonuclear leukocyte defence system. MPO catalyses the production of the oxidant hypochlorous acid and is thought to contribute to Alzheimer's pathology through oxidation of either ß amyloid or APOE (86). These events could result in direct neuronal damage or promote insoluble amyloid complexes. It is interesting to note that the E4 isoform of APOE is the most readily oxidized and neurotoxic, conferring upon it a contributory role to increased risk for the disease (87). Microglia in normal brain tissue do not express MPO but it has been found to be expressed in the microglia of the senile plaques and neurons of the hippocampus and superior frontal gyrus within Alzheimer's brains (88). The gene for MPO resides on chromosome 17q23.1 and recently a polymorphism (G463A) has been associated with a 1.57-fold increased risk for AD in individuals carrying the MPO GG genotype (87). Novel polymorphisms found within the TAU gene have been associated with an increased risk for AD disease. A case–control study looking at the TAU IVSII+90G
A polymorphism showed a significant association between early age of onset in males and the possession of the A allele. This suggests that the risk factor for developing the disease may be modified as a result of both age and gender (89). A further case–control study examining the IVSII+34 GA polymorphism showed a 5-fold increased risk in individuals who carried both the APOE4 allele and were either heterozygous/homozygous for the G allele (GA, GG). This would suggest that the combined effect of both these alleles may have a significant outcome on Alzheimer's pathology (90). Hyperdiploidy of chromosome 17 would also result in over-expression of both the MPO and TAU gene and may be expected to contribute to the aetiology of the disease.
Mutations within genes such as APOE, CYP46A1 and ABCA1, which play a role in cholesterol and phospholipid metabolism, have been investigated and shown to have associations with AD. Recently a strong association between early-onset Alzheimer's and polymorphisms within the ABCA2 gene have been shown adding support for the role of these genes in Alzheimer's pathology (91).
Alpha-1-antichymotrypsin (ACT) is a protease inhibitor and is associated with astrocyte activity and the deposition of amyloid plaques. The G646T polymorphism within the promoter region of ACT has been shown to be associated with a higher risk for early-onset AD. This higher risk factor occurs independently of the APOE 4 genotype; however the rate of cognitive decline is elevated in those individuals homozygous for the ACT polymorphism and who also possess the APOE 4 genotype (92).
It has recently been suggested through the results of linkage analysis that the Ubiquilin 1 gene located at 9q22 could be a possible susceptibility gene for increased risk for AD (93). It plays an intriguing role in the degradation of proteins and has been shown to interact with both PSEN1 and PSEN2, promoting the accumulation of presenilin in vitro in cells over-expressing both Ubiquilin 1 and PSEN2 (94). Further investigations will need to be undertaken to further assess the role of Ubiquilin as a potential candidate risk gene for AD.
It is apparent that numerous families exist that possess the Alzheimer's phenotype but do not conform to the current pattern of known Alzheimer's genetics. This would indicate that there are as yet other loci waiting to be discovered that can act as genetic determinants for FAD.
Although much emphasis has been placed on the role of APOE as a risk factor, this is because of the current body of evidence that firmly establishes it in its role as a susceptibility gene relative to other known or unknown genetic risk factors. Other genes that have been reviewed are currently potential susceptibility genes but their status as definite risk factors can only be confirmed or refuted as additional evidence comes to light resulting from further investigation e.g. mutations within the progranulin gene on chromosome 17 have recently been found to play a role in dementia and may eventually be classified as a definite risk factor once these initial observations have been replicated (95).
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Genomic instability events |
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Aneuploidy
Damage to the genome could lead to altered gene dosage and gene expression as well as contribute to the risk of accelerated cell death in neuronal tissues. DNA damage events such as micronuclei formation, which are biomarkers of chromosome malsegregation and fragility, were found to be elevated in lymphocytes from individuals suffering from AD (96
). Micronuclei from Alzheimer's patients tended to be centromere positive relative to normal controls when examined with a centromeric probe, indicating whole chromosome loss rather than breakage, suggesting individual susceptibility to aneuploidy events possibly due to microtubule dysfunction (96,97). Fluorescent probes for chromosome 13 and 21 were hybridized to lymphocyte preparations from Alzheimer's patients and showed an elevation in aneuploidy for both chromosomes, but in particular for chromosome 21 (97,98). Further studies investigating fibroblasts from both spontaneous and familial Alzheimer's subjects carrying mutations in the genes PSEN1, PSEN2, and APP were found to have a 2-fold increase in the incidence of aneuploidy involving both chromosome 18 and 21 when compared to controls (99). It is possible that chromosome aneuploidy, particularly for chromosome 21, could be one of the mechanisms underlying both AD and the dementia that occurs in Down's syndrome patients (100).
Down's syndrome is diagnosed cytogenetically as being aneuploid for chromosome 21; individuals develop dementia that is histopathologically indistinguishable from AD during the third or fourth decade of life (101). Cells containing trisomy 21 are found in both Down's syndrome and Alzheimer's patients. Over-expression of the APP gene could lead to over-production of the Aß42 following cleavage by the secretase enzymes, which is causally related to plaque formation in both Down's syndrome and Alzheimer's brains (102). APP processing is also altered in terms of the ratio of Aß42 over the normal 40 amino acid ß amyloid peptide (Aß40), resulting in the increased production of the more amyloidogenic and neurotoxic form Aß42 (102). It has been proposed that individuals who are susceptible to AD may harbour significant numbers of trisomy 21 neural stem cells that with the passage of time, can result in brain segments having a Down's syndrome phenotype which may contribute to the aetiology of the disease (100). It is possible that like Down's syndrome this low-level mosaicism may have originated in utero as a result of age-related parental non-disjunction, or under dietary conditions such as low-folate status that has been shown to increase the rate of chromosome 17 and 21 aneuploidy (103). Alternatively, mosaicism may arise in those individuals who have a predisposition to aneuploidy events, which involve unequal mitotic segregation in aneuploid susceptible tissues within areas of the brain undergoing post-maturation neurogenesis. Such areas that may be affected include the dendate gyrus of the hippocampus that is involved in short-term memory and learning and is readily affected in the initial stages of Alzheimer's. These individuals are predisposed to develop the disease, but over a longer period of time due to the smaller population of mosaic cells that over-express genes that contribute to the symptoms of the disease such as APP and TAU. These hypotheses are biologically plausible however further evidence needs to be acquired to determine conclusively the potential roles of these mechanisms in Alzheimer's pathology. Mutated presenilin genes that contribute to early-onset FAD (104–106), produce proteins that have been found to be localized within the nuclear membrane, centrosomes and interphase kinetochores indicating a role in chromosome segregation and organization (99,106). Mutations within these genes that predispose to early-onset FAD (104–106), may alter the ability of the resultant proteins to lock on and release chromosomes to the nuclear membrane at the appropriate time during mitosis, hence leading to errors in chromosome segregation (106).
Aneuploid cells may be susceptible to programmed cell death directly leading to neurodegeneration by over-expressing presenilins and APP that increase the cells sensitivity to apoptotic stimuli (107). These cells having succumbed to apoptosis may then give rise to areas of inflammation, induced by the cerebral phagocytes microglia, that surround the neuritic plaques. Microglia induce astrocytes by expressing Interleukin-1. The astrocytes in turn express -chymotrypsin, which promotes further neurotoxic amyloid plaque formation (108,109).
Hyperphosphorylation of tau leads to a breakdown of the microtubule system, which may give rise to aneuploidy by causing defects in the mitotic spindle. Potentially an elevation in chromosome 17-aneuploidy could lead to an over-expression of the TAU gene resulting in abnormal production and accumulation of the protein initiating further neurofibrillary tangle formation. Additional chromosome 17-aneuploidy may occur as a result of elevated levels of oxidative stress that are also associated with AD (110).
Telomere shortening, oxidative stress, breakage fusion bridge cycles and gene amplification
Telomeres are hexanucleotide repeats that are located at the end of eukaryotic chromosomes and their dysfunction has been implicated in AD. They play an important role in maintaining genomic stability and preventing chromosomes from becoming tangled and protect the chromosomal ends from being recognized as a site of DNA damage (111,112). During DNA replication somatic cells lose telomeric repeats after every cell division undertaken, and therefore telomere length may serve as a marker of a cells replicative history. Telomerase and associated proteins prevent telomeres shortening in extreme proliferative cell types such as cancer cell lines and stem cells. Telomerase is also present in other cells such as lymphocytes but at levels that cannot prevent shortening of the telomeres leading to replicative senescence (111,113).
It has been shown that telomere shortening is associated with an elevated incidence of certain cancers (head, neck, lungs, epithelial cancers such as prostate) and is exacerbated by other risk factors such as ageing and smoking (114). Other studies have shown that individuals exhibiting accelerated telomere shortening die 4–5 years earlier and have higher incidences of heart disease compared to age and gender matched controls (115). Telomere shortening results in a decrease in lymphocyte proliferation activity and has been shown to impair the immune system in AD. Telomere shortening is also associated with T cell clonal expansion involving immune responses to auto antigens in Alzheimer's patients. Panossian et al. (112) found significant telomere shortening in peripheral blood mononuclear cells from Alzheimer's patients compared to controls. T cell telomere length correlated with deficits in cognitive function, as assessed by the mini mental state examination, which determines cognitive decline (112). Telomeres have also been found to be significantly shorter in leukocytes of individuals suffering from vascular dementia compared to age and gender matched controls (116). Genomic instability resulting from telomere loss may lead to gene over-expression as a result of gene amplification, through the repeated breakage and fusion of chromosomes that occur through the breakage/fusion/bridge cycle (BFB) (117–119).
The cycle can be initiated by telomere end fusions with short telomeres, which fuse to form a dicentric chromosome. If the fusion occurs between homologous chromosomes the dicentric chromosome will contain two copies of a gene positioned between two centromeres. These centromeres are drawn to opposite poles during anaphase and break unevenly as cytokinesis occurs. This results in a chromosome containing two copies of a gene and a fragment that has lost its initial gene copy. These multiple gene containing chromatids may further fuse during interphase to form another dicentric chromosome increasing its gene complement which is then replicated during nuclear division resulting in further amplification following the next BFB cycle (120,121) (Figure 8).
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It has been shown that smaller chromosomes such as chromosome 17 and 21 have shorter telomeres than their larger genomic counterparts (122
). It may be possible that these smaller chromosomes may be more susceptible to undergo BFB cycles (123), resulting in over-expression of Alzheimer's-related genes such as TAU and APP. This hypothesis has biological plausibility but further evidence is required in order to determine conclusively its role in Alzheimer's pathology.
Differences in the telomere length of human chromosomes may be a contributory factor relating to a higher incidence of specific chromosome aneuploidy (124). Telomeres are implicated in the positioning of chromosomes by forming a point of attachment to the nuclear membrane within the interphase nucleus and in chromatid segregation during mitosis. Smaller chromosomes with shorter telomeres such as chromosomes 17 and 21 may be more susceptible to aneuploidy events as a result of mitotic non-disjunction events or faulty interphase chromosomal positioning. It is also possible that BFB cycle events involving dicentric chromosomes containing homologous chromosomes may result in aneuploidy through the formation of chromosomal end-to-end fusions resulting in subsequent gene amplification (122,125). It has also been shown that telomere shortening is accelerated under conditions of oxidative stress (116,126). Some of the measurable genome instability events are seen in Figure 9.
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Oxidative stress is now accepted as playing a key role in the pathology of AD (127
–129), and is the result of an imbalance between elevated free radical production and a decrease in either free radical scavenging or the mechanisms used to repair oxidized macromolecules. This leads invariably to cellular dysfunction and eventual cell death.
Free radicals such as the hydroxyl ion, hydrogen peroxide and peroxynitrite have been shown to induce cytotoxicity by interacting with and damaging major components of the cell through oxidation of lipids and nucleic acids including the nucleus, membrane and cytoplasmic proteins, mitochondrial DNA, as well as, being involved with neurotoxic metal complexes, thereby compromising their cellular function. Neurons appear to be particularly vulnerable to the damaging effects of free radicals, they are known to have low levels of natural antioxidants such as glutathione which would aid in protecting the neuron (43), as well as requiring an increased oxygen demand to maintain brain metabolism (130). The elevated oxygen environment is ideal as it can be used as a substrate in reactions with compounds that are primary producers of free radicals e.g. ß amyloid.
APOE may be beneficial by reducing neuronal death caused by ß amyloid and hydrogen peroxide by acting as an antioxidant (131). Of the three allelic states the E2 isoform is the most effective antioxidant with the E4 allele (associated with late-onset AD) being the least effective in its protective capacity (132). However it has also been shown that the APOE4 isoform is the most sensitive to free radical attack compared with the more resilient E2 isoform and that peroxidation levels in the brains of AD patients that possessed the E4 allele are elevated compared to those individuals possessing either the E2 or E3 allele (133).
It has recently been shown using a modified version of the comet assay that there is a 2-fold increase in levels of DNA damage and oxidized DNA bases (pyrimidines and purines) in leukocytes of individuals with mild cognitive impairment (MCI) and AD when compared to matched-controls (134). MCI individuals display the initial signs of cognitive decline (memory loss) but not to the extent that they cannot pursue or participate in everyday activities. This suggests that oxidative damage occurs at the early stages of AD, as MCI patient's progress to Alzheimer's with an estimated probability of 50% within 4 years or 12% per year (134,135), suggesting that MCI represents the early stages of the disease and that oxidative stress directly contributes to disease pathology.
A further marker of oxidative stress 8-Hydroxy-2-deoxyguanosine (8-OHdG) is elevated in both peripheral tissues of MCI and AD (129,134,136). It has also been shown that oxidative stress is clear within the post mortem Alzheimer's brain where an increase in mitochondrial and nuclear oxidative damage is evident (44,135). Interestingly it appears that an increase in both 8-OHdG and 3-Nitrotyrosine within the Alzheimer's brain occur prior to the development of both tangles and plaques indicating that oxidative stress may be one of the initiating factors leading to further genomic instability (44,136,137).
The genome instability model of AD outlined in Figure 10 allows for the possibility that certain disease states may have already been pre-determined in utero. Aneuploidy prone individuals (either as a result of individual genome or micronutrient deficiency e.g. folate) can give rise to low levels of mosaicism for individual chromosomes such as chromosome 17 and 21. Gene amplification may occur as a result of telomere end fusions (Figure 8). Aneuploidy may result in additional copies of both APP and TAU leading to the altered homeostasis of both these proteins. The Alzheimer's phenotype becomes apparent in stem cells, which differentiate into neural stem cells with abnormal APP and tau levels, which with the passage of time influence the initial stages of neurodegeneration. These stem cells could also differentiate into non-neural somatic cells (e.g. buccal or fibroblast which having an elevated tau and APP level) and could be used to study genomic instability events such as elevated micronuclei and aneuploidy.
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Dietary and nutrigenetic factors that affect Alzheimer disease risk |
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 TopIntroductionClinical diagnosisTau and neurofibrillary tanglesß amyloid and neuritic...Amyloid cascade hypothesis:...Genetics of ADGenomic instability events Dietary and nutrigenetic factors... ConclusionReferences |
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B vitamins
Many case–control studies have shown that Alzheimer's patients have been found to be deficient in certain micronutrients such as folate, vitamin B12 but have elevated levels of the sulphur based amino acid homocysteine (138
,139). These factors are associated with increased micronucleus formation and the alteration of methylation patterns that could modify gene expression (120,140,141). Folate and vitamin B12 play an important role in DNA metabolism. Folate is the methyl donor for the conversion of dTMP from dUMP, which is required for DNA synthesis and repair. Under conditions of low folate, dUMP accumulates producing DNA strand breaks and micronucleus formation as a result of uracil misincorporation into DNA in place of thymine (120,142). Both folate and vitamin B12 are required in the synthesis of methionine through the remethylation of homocysteine, and in the synthesis of S-adenosyl methionine (SAM), which is involved in maintaining genomic methylation patterns that determine gene expression (143). Folate deficiency reduces SAM resulting in the depletion of cytosine methylation in DNA, and thereby elevating homocysteine levels. Additionally folate deficiency has been shown to increase trisomy of chromosome 17 and 21, which code for the TAU and APP genes, respectively (103).
Hyperhomocysteinemia has been shown to be a strong independent risk factor for AD in a number of epidemiological studies (144–148). It appears that nervous tissue may be extremely sensitive to excessive homocysteine as it promotes excitotoxicity and damages neuronal DNA giving rise to apoptosis (149). Studies have also shown a strong correlation between a reduction in hippocampal width, which is associated with short-term memory loss, and concentrations of plasma homocysteine (150). Recently MRI measurements have shown that an inverse relationship exists between plasma homocysteine and cortical and hippocampal volume (151). The above findings have been interpreted as involving neuronal damage within the hippocampal regions leading to memory loss, which is characteristic of AD. Elevated homocysteine has also been implicated as playing a role in an iron dysregulation/oxidative stress cycle that is thought to be central to the pathogenesis of the disease (152).
Homocysteine levels are usually maintained within physiologically correct limits by remethylation to methionine in a reaction involving folate and vitamin B12 (Figure 11). Homocysteine can also be converted to cystathionine by the involvement of the enzyme cystathionine ß-synthase, resulting in increased levels of glutathione which is a natural anti oxidant (153).
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Studies have shown that supplementation with B group vitamins such as folate, B12 and B6 reduce the levels of homocysteine in patients suffering from AD (138
,154). It has also been shown that low levels of B12 are associated with reduced memory recall in those individuals who are APOE4 carriers, who are at a greater risk of developing dementia. These individuals may derive benefits in memory recall by enhancing supplementation of both folate and B12 (155). Niacin (vitamin B3) has a role in DNA synthesis and repair as well as in neural cell signalling. Recently it has been implicated in reducing cognitive decline and protecting against the onset of AD. Individuals consuming niacin in excess of 22.4 mg/day were estimated to be 80% less likely to suffer cognitive decline when compared to groups consuming lesser amounts (156). Niacin is also essential as a precursor for Nicotinamide adenine dinucleotide (NAD) an essential cofactor for poly ADP ribose polymerase, which has been shown to play an essential role in memory function of the mollusc Aplysia (157). NAD dependent sirtuins such as SIRT1 have been implicated as one of the key regulatory factors influencing extended lifespan under conditions of calorific restriction. It has also recently been shown that SIRT1 promotion may influence Alzheimer neuropathology by activating kinases that regulate the processing of APP (158). Although these initial results are promising, further studies need to be performed to verify conclusively the role of niacin as an effective therapy in the protection against AD.
Mutations in folate, methionine metabolism genes
As AD is related to low folate, B12 and elevated homocysteine levels, investigators have looked towards genetic polymorphisms within the folate methionine pathway (Figure 11) to explain these micronutrient differences. Polymorphisms within these genes may alter folate metabolism as a result of reduced enzyme activity. A polymorphism resulting in altered folate metabolism and increased homocysteine occurs within the methylenetetrahydofolate reductase gene (MTHFR). MTHFR converts 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, which donates a methyl group for remethylation of homocysteine to methionine. A common polymorphism involves the C to T transition at position 677 resulting in an alanine to valine substitution and reduced enzyme activity. Enzyme activity of the heterozygote CT and the homozygote TT is reduced by 35 and 70%, respectively when compared to the normal CC genotype (159). Homozygosity for the T allele occurs in 9% of Caucasian populations and is associated with reduced enzyme activity resulting in mild to moderately elevated homocysteine levels (160). Other polymorphisms within the MTHFR gene include A1298C and G1793A, which may have regulatory roles in the activity of the enzyme (161). In determining the risk factor of C677T in relation to AD no association between C677T and increased susceptibility to Alzheimer's risk was found (162). However if combinations of polymorphisms within a gene are considered together then sometimes effects become apparent that are not always evident if those same polymorphisms are considered in isolation. Wakutani et al. (163) found that the MTHFR 677C-1298C-1793G haplotype to be protective in Japanese populations against late-onset AD (163). Methionine synthase (MS) catalyses the remethylation of homocysteine to methionine. The A2756G polymorphism within the MS gene has been shown to be associated with hyperhomocysteinemia, and to be an APOE4 independent risk factor for AD (164). This implies that alterations within the genes for enzymes of the homocysteine metabolic pathway are involved in Alzheimer's pathogenesis (165).
Methylation
Changes in methylation patterns of ageing cells involve global hypomethylation and CpG island hyper-methylation. Folate deficiency decreases S-adenosyl methionine (SAM) levels, which act as a methyl donor for gene regulation, thereby potentially impairing methylation pathways. Individuals with AD were found to have reduced levels of SAM both in the brain and cerebrospinal fluid (166). SAM also activates the enzyme cystathionine ß-synthase (CBS), which is highly expressed in the hippocampus and cerebellum (167). CBS reduces homocysteine to cystathionine and L-cysteine producing hydrogen sulphide which acts as a neural modulator by facilitating hippocampal long-term potentiation and therefore may have a role in learning (167,168). Hydrogen sulphide has also been shown to protect neurons indirectly from oxidative stress by promoting the production of the potent antioxidant glutathione (169). CBS activity is reduced in AD patients, resulting in a decrease in hydrogen sulphide and an elevation in homocysteine, which may play a role in the cognitive decline associated with the disease (168,170).
It has been shown that low satellite DNA methylation leads to aneuploidy and breakage of chromosome 1, which codes for PSEN2 (141,171), whereas low genome promoter methylation leads to increased expression of PSEN1 and BACE (ß secretase) resulting in elevated ß amyloid production (140,172). It has also been shown that a reduced DNA methylation status in the APP gene results in increased production of the Aß42, which leads to further elevated plaque deposition (173). Moreover, when methylation status is increased by the addition of SAM a normalization of the PSEN1 and BACE expression occurs in vitro thus restoring normal gene expression leading to a reduction in ß amyloid levels (140). Alzheimer's-related genes may also be amplified via BFB cycles caused by folate deficiency (120) although direct evidence for this possibility has yet to be published. Therefore promoter hypomethylation, aneuploidy and gene amplification resulting from deficiencies in folate and B12 and elevated homocysteine, may contribute to abnormally increased expression of genes relating to AD.
Antioxidants
Oxidative stress and inflammation have been implicated as some of the main contributing factors in the pathogenesis of AD. Recently a number of studies have come to light that show the positive effects of dietary antioxidants as an aid in reducing potential neuronal damage by free radicals (43,174,175).
The Cache County study has shown that combined supplementation with antioxidant vitamins C and E may reduce the prevalence of AD (176). It has recently been shown that hippocampal gene expression in mice can be influenced by a deficiency in vitamin E. Important genes regulated by vitamin E were associated with the clearance of ß amyloid, programmed cell death and neurotransmission, suggesting a protective role on Alzheimer's progression (177).
Curcumin is the yellow phenolic pigment in the Indian curry spice, turmeric. It has been shown to possess both antioxidant and anti-inflammatory properties, as well as, the ability to reduce Aß42 toxicity by preventing the formation of ß42 oligomers leading to amyloid plaques (178,179). In animal models curcumin was shown to inhibit amyloid plaque formation by blocking the aggregation of the ß fibrils that make up the structure of the amyloid plaque (179,180). Curcumin may also prevent the formation of plaques by behaving as a chelator, binding metals such as copper and iron that have been shown to form complexes with Aß42 resulting in oxidative stress and free radical formation (181).
Out of 60 fruit and vegetables analysed for their antioxidant capability, blueberries rated highest in their ability to mop up free radicals (182). Blueberries contain high levels of the antioxidant anthocyanins; these prevent damage to the collagen matrix of cells by forming complexes with collagen fibres, to form a more stable structure that is more resistant to the damaging effects of free radicals (183). In animal models it appears that blueberries not only protect against oxidative damage, but also play a vital role in preventing cognitive decline in mice genetically engineered to develop the amyloid plaques typical of AD (183,184).
Proanthocyanins, a group of polyphenol compounds that occur within grape seed extract (GSE), have been found to be up to 20 times more effective in scavenging free radicals than vitamin E, and up to 50 times more effective than vitamin C (185). In experiments involving brain cells from rats, it was shown that cells treated with GSE and then exposed to ß amyloid were protected against free radical accumulation and neuronal damage, compared to GSE untreated brain cells that subsequently died as a result of free radical accumulation (186). It has also been shown that GSE used as a dietary supplement affects certain proteins within the healthy brain that may serve to protect against brain ageing and future age-related dementia (187).
Green tea has been shown to contain antioxidant flavonoids that can protect against neuronal damage caused by free radicals. One of the mechanisms by which green tea offers protection, is by its action as a chelating agent, binding excess iron levels, which serve to reduce the amount of oxidative stress caused from free radical production (188).
Animal studies involving Alzheimer's transgenic mice show that a green tea flavonoid epigallocatechin-3-gallate (EGCG) has the ability to reduce levels of ß amyloid and neuronal plaques within the brain (189). This suggests that dietary supplementation with EGCG may be effective in preventing plaque formation that is characteristic of the disease.
Acetylcholine is a neurotransmitter that is reduced in AD. Green tea has been shown to inhibit the activity of certain brain enzymes associated with reduced cognitive function and the development of AD (190). Green tea drinkers were found to have lower activity in both acetylcholinesterase which breaks down acetylcholine and butylcholinesterase which has been found in brain deposits of Alzheimer's patients ß secretase an enzyme that plays an integral role in the aberrant proteolysis of APP resulting in plaque formation was also found to have lower enzyme activity in individuals exposed to green tea flavonoids (190). A study investigating cognitive function and green tea consumption revealed that individuals who drank >2 cups of green tea a day had a 50% lower chance of developing memory disorders compared to individuals who drank <3 cups a week. Cognitive function was determined by the use of the mini mental state examination, a method that is widely used to assess changes in the cognitive status of individuals (191).
Continued studies into the chemo-preventative components of foodstuffs are important, in order to quantify their role as protective therapies for AD.
Copper, iron, zinc, selenium and aluminium
Recently, associations between metals such as copper (Cu2+), iron (Fe2+) and zinc (Zn2+) and amyloid plaques have been proposed as a potential mechanism to explain the aetiology of AD. Metals play a major catalytic role in the generation of free radicals, which are known to be toxic and induce cellular damage at both DNA and protein levels. High concentrations of Cu2+, Zn2+ and Fe2+ are found in the cerebral neocortex. (192). These ions are released during neurotransmission resulting in increased ion concentration within the synaptic region (193). It has been shown that the concentration of these ions is elevated within the extracellular ß amyloid plaques (194–196). Both copper and iron initiate the aggregation of ß amyloid peptides under slightly acidic conditions (197). The precipitation and redox potential of ß amyloid can be modified through reduction reactions utilizing oxygen as a substrate to produce hydrogen peroxide (194,197,198). Hydrogen peroxide is highly permeable and diffusible, whereupon it can induce apoptosis and necrosis and produce highly reactive hydroxyl ions bringing about further cellular damage (199). The resultant hydrogen peroxide offered a possible mechanism to explain neurotoxicity and cell death mediated by the ß amyloid–metal complexes (198).
Zinc2+, unlike copper and iron, is redox inert, but is still found in elevated levels within the amyloid plaques (194–196,200). It appears that zinc, like copper and iron, can initiate amyloid precipitation, however it has an inhibitory effect on hydrogen peroxide production by competing with other metals for active sites on the ß amyloid (197,201). It is thought that zinc leads to ß amyloid aggregation at the physiological pH of 7.4 and this results in an inability of the plaques to be cleared or broken down. Zinc has been shown to have some antioxidant activity in relation to minimizing the neurotoxic effect of the Aß42; however it is not completely effective in alleviating peroxide production and apoptosis. It would appear as if zinc could potentially play a dual role depending on the concentration of the ion present. At lower levels it appears to render ß amyloid less toxic whereas at elevated levels it contributes to plaque formation.
Further support for the involvement of zinc in the histopathology of AD was demonstrated by Lee et al. (202) who showed a reduction in ß amyloid production in the brains of mice that were deficient for zinc transporters which are required for transport of zinc into synaptic vesicles. It has been proposed that release of excessive synaptic zinc during neurotransmission could contribute to plaque formation, which is dominant to the histopathology of AD (202). The selenium, present in Brazil nuts, tuna and some meats, has been shown to be inversely associated with levels of homocysteine. It was found that serum selenium had a greater regulatory capacity to minimize homocysteine levels in elderly persons, even when compared with folate regulatory levels (203). Selenium is also indirectly responsible for maintaining levels of antioxidants such as vitamins C and E intact via the enzyme glutathione peroxidase.
The metalobiology of aluminium and its role as a risk factor in AD has been a controversial issue. The purported relationship between aluminium and AD was based on studies reporting the detection of aluminium in the neurofibrillary tangles (204,205) and neuritic plaques (35,206). However later studies found no evidence of aluminium in the plaques of Alzheimer patients (207). Similar patterns emerge from epidemiological studies investigating environmental levels of aluminium in drinking water. Some studies showed a positive association whereas others reported no such relationship (208,209). To date the evidence is considered circumstantial demonstrating no definite causal relationship between aluminium and AD. Government regulatory agencies together with the medical research community review the current evidence at regular intervals, but to date no public health recommendations have been put forward regarding aluminium and AD risk.
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Conclusion |
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AD was once described as like being slowly immersed into a dissipating fog that surrounds everything that is familiar and everything that characterizes the make up of an individual (210
). As the fog descends and thickens so everything loses its form and function. As we stare into the 21st Century we are faced with a disease that is predicted to make a pronounced impact on our lives both socially and economically. The prospect of an early and conclusive diagnostic test based on abnormal expression of APP, tau and genome instability markers is essential in order to identify individuals who are presymptomatically at an increased risk for developing AD. Once this has been achieved it may allow us to develop and implement effective preventative measures against AD, as well as other degenerative diseases caused by an excessive genome damage rate. |
Acknowledgments |
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The authors would like to thank Associate Professor Michael Roberts for his valuable contribution and comments during the compilation of this manuscript. Figure 1 was found at History of Alzheimer's disease (hod.kcms.msu.edu), whereas Figs 2, 3 and 6 were obtained from Pubs.acs.org, pathology.VCU.edu and CNSforum.com.
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Notes |
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*To whom correspondence should be addressed. Email: Michael.Fenech{at}csiro.au; and Philip.Thomas{at}csiro.au
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References |
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-
1. Maurer K., Volk S., Gerbaldo H. (1997) Auguste D and Alzheimer's disease. Lancet 349:1546–1549.[CrossRef][Web of Science][Medline]
2. Alzheimer A. (1906) Uber Einen eigenartigen schweren Erkrankungsprozeb der Hirnrinde. Neurologisches cenrealblatt 23:1129–1136.
3. Burns A., Byrne E.J., Maurer K. (2002) Alzheimer's disease. Lancet 360:163–165.[CrossRef][Web of Science][Medline]
4. Ferri C.P., Prince M., Brayne C., et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117.[CrossRef][Web of Science][Medline]
5. Wimo A., Winblad B., Aguero-Torres H., von Strauss E. (2003) The magnitude of dementia occurrence in the world. Alzheimer. Dis. Assoc. Disord. 17:63–67.[Medline]
6. Henderson A.J. and Jorm A.F. (1998) Dementia in Australia. Aged and Community Care Service Development And Evaluation Report No 35(AGPS, Canberra).
7. Delaying the onset of Alzheimer's disease: projections and issues. Access Economics August 2004.
8. Kawas C.H. (2003) Clinical practice. Early Alzheimer's disease. N. Engl. J. Med. 349:1056–1063.
9. Ritchie K. and Lovestone S. (2002) The dementias. Lancet 360:1759–1766.[CrossRef][Web of Science][Medline]
10. St George-Hyslop P.H. (2000) Piecing together Alzheimer's. Sci. Am. 283:76–83.[Web of Science][Medline]
11. Lederman R.J. (2000) What tests are necessary to diagnose Alzheimer disease? Cleve. Clin. J. Med. 67:615–618.[Web of Science][Medline]
12. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E.M. (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939–944.
13. Small G.W., Rabins P.V., Barry P.P. (1997) Diagnosis and treatment od ALzheimer disease and related disorders. JAMA 278:1363–1371.
14. Santacruz K.S. and Swagerty D. (2001) Early diagnosis of dementia. Am. Fam. Physician 63:703–713 717–718.[Web of Science][Medline]
15. Khalil Z. (2004) Early diagnosis of dementia. Melbourne Health Research Week, Melbourne.
16. Khalil Z., Poliviou H., Maynard C.J., Beyreuther K., Masters C.L., Li Q.X. (2002) Mechanisms of peripheral microvascular dysfunction in transgenic mice overexpressing the Alzheimer's disease amyloid Abeta protein. J. Alzheimers. Dis. 4:467–478.[Medline]
17. Higuchi M., Iwata N., Matsuba Y., Sato K., Sasamoto K., Saido T.C. (2005) (19)F and (1)H MRI detection of amyloid beta plaques in vivo. Nat Neurosci. 8:527–533.[CrossRef][Web of Science][Medline]
18. Iqbal K., Grundke-Iqbal I., Smith A.J., George L., Tung Y.C., Zaidi T. (1989) Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc. Natl Acad. Sci. USA 86:5646–5650.
19. Goedert M., Spillantini M.G., Jakes R., Rutherford D., Crowther R.A. (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3:519–526.[CrossRef][Web of Science][Medline]
20. Iqbal K., Alonso A.C., Gong C.X., Khatoon S., Pei J.J., Wang J.Z., Grundke-Iqbal I. (1998) Mechanisms of neurofibrillary degeneration and the formation of neurofibrillary tangles. J. Neural. Transm. Suppl. 53:169–180.[Medline]
21. Gomez-Ramos A., Smith M.A., Perry G., Avila J. (2004) Tau phosphorylation and assembly. Acta. Neurobiol. Exp. (Wars.) 64:33–39.
22. Cash A.D., Aliev G., Siedlak S.L., et al. (2003) Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am. J. Pathol. 162:1623–1627.
23. Schellenberg G.D. (1995) Genetic dissection of Alzheimer disease, a heterogeneous disorder. Proc. Natl Acad. Sci. USA 92:8552–8559.
24. Hogg M., Grujic Z.M., Baker M., et al. (2003) The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta. Neuropathol. (Berl.) 106:323–336.[CrossRef][Medline]
25. Lippa C.F., Zhukareva V., Kawarai T., et al. (2000) Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation. Ann. Neurol. 48:850–858.[CrossRef][Web of Science][Medline]
26. Buee L., Bussiere T., Buee-Scherrer V., Delacourte A., Hof P.R. (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain. Res. Brain. Res. Rev. 33:95–130.[CrossRef][Medline]
27. Hutton M., Lendon C.L., Rizzu P., et al. (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705.[CrossRef][Medline]
28. Koo E.H. (2002) The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog? Traffic 3:763–770.[CrossRef][Web of Science][Medline]
29. Howlett D.R., Simmons D.L., Dingwall C., Christie G. (2000) In search of an enzyme: the beta-secretase of Alzheimer's disease is an aspartic proteinase. Trends. Neurosci. 23:565–570.[CrossRef][Web of Science][Medline]
30. Bennett B.D., Denis P., Haniu M., Teplow D.B., Kahn S., Louis J.C., Citron M., Vassar R. (2000) A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. J. Biol. Chem. 275:37712–37717.
31. Selkoe D.J. (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81:741–766.
32. Periz G. and Fortini M.E. (2000) Proteolysis in Alzheimer's disease. Can plasmin tip the balance? EMBO Rep. 1:477–478.[Web of Science][Medline]
33. Vassar R. and Citron M. (2000) Ab-generating enzymes: recent advances in beta and gamma secretase research. Neuron 27:419–422.[CrossRef][Web of Science][Medline]
34. Selkoe D.J. (2004) Alzheimer disease: mechanistic understanding predicts novel therapies. Ann. Intern. Med. 140:627–638.
35. Masters C.L., Multhaup G., Simms G., Pottgiesser J., Martins R.N., Beyreuther K. (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 4:2757–2763.[Web of Science][Medline]
36. Cataldo A.M., Petanceska S., Terio N.B., Peterhoff C.M., Durham R., Mercken M., Mehta P.D., Buxbaum J., Haroutunian V., Nixon R.A. (2004) Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol. Aging 25:1263–1272.[CrossRef][Web of Science][Medline]
37. Haass C., Koo E.H., Mellon A., Hung A.Y., Selkoe D.J. (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357:500–503.[CrossRef][Medline]
38. Tomita S., Kirino Y., Suzuki T. (1998) Cleavage of Alzheimer's amyloid precursor protein (APP) by secretases occurs after O-glycosylation of APP in the protein secretory pathway. Identification of intracellular compartments in which APP cleavage occurs without using toxic agents that interfere with protein metabolism. J. Biol. Chem. 273:6277–6284.
39. Wirths O., Multhaup G., Bayer T.A. (2004) A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide—the first step of a fatal cascade. J. Neurochem. 91:513–520.[CrossRef][Web of Science][Medline]
40. Billings L.M., Oddo S., Green K.N., McGaugh J.L., Laferla F.M. (2005) Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 45:675–688.[CrossRef][Web of Science][Medline]
41. Loo D.T., Copani A., Pike C.J., Whittemore E.R., Walencewicz A.J., Cotman C.W. (1993) Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc. Natl Acad. Sci. USA 90:7951–7955.
42. Forloni G. (1993) beta-Amyloid neurotoxicity. Funct. Neurol. 8:211–225.[Medline]
43. Christen Y. (2000) Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71:621S–629S.
44. Mecocci P., MacGarvey U., Beal M.F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann. Neurol. 36:747–751.[CrossRef][Web of Science][Medline]
45. Lin K.-F., Chang R.C.-C., Suen K.-C., So K.-F., Hugon J. (2004) Modulation of calcium/calmodulin kinase-II provides partial neuroprotection against beta-amyloid peptide toxicity. Eur. J. Neurosci. 19:2047–2055.[CrossRef][Web of Science][Medline]
46. Mattson M.P. (2004) Pathways towards and away from Alzheimer's disease. Nature 430:631–639.[CrossRef][Medline]
47. Lu D.C., Rabizadeh S., Chandra S., Shayya R.F., Ellerby L.M., Ye X., Salvesen G.S., Koo E.H., Bredesen D.E. (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat. Med. 6:397–404.[CrossRef][Web of Science][Medline]
48. Ivins K.J., Thornton P.L., Rohn T.T., Cotman C.W. (1999) Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8. Neurobiol. Dis. 6:440–449.[CrossRef][Web of Science][Medline]
49. Nakagawa T., Zhu H., Morishima N., Li E., Xu J., Yankner B.A., Yuan J. (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103.[CrossRef][Medline]
50. Mattson M.P., Keller J.N., Begley J.G. (1998) Evidence for synaptic apoptosis. Exp. Neurol. 153:35–48.[CrossRef][Web of Science][Medline]
51. Hardy J., Duff K., Hardy K.G., Perez-Tur J., Hutton M. (1998) Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau. Nat. Neurosci. 1:355–358.[CrossRef][Web of Science][Medline]
52. Hardy J. and Allsop D. (1991) Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends. Pharmacol. Sci. 12:383–388.[CrossRef][Medline]
53. Hardy J. (1997) Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20:154–159.[CrossRef][Web of Science][Medline]
54. Schonheit B., Zarski R., Ohm T.G. (2004) Scientific progress and a Hardy paradigm-the ‘amyloid cascade hypothesis’ revisited. Neurobiol. Aging 25:743–746.[CrossRef]
55. Schonheit B., Zarski R., Ohm T.G. (2004) Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol. Aging 25:697–711.[CrossRef][Web of Science][Medline]
56. Hardy J. and Selkoe D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356.
57. Hardy J. (2001) The genetic causes of neurodegenerative diseases. J. Alzheimers Dis. 3:109–116.[Medline]
58. Scheuner D., Eckman C., Jensen M., et al. (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2:864–870.[CrossRef][Web of Science][Medline]
59. Wisniewski K.E., Wisniewski H.M., Wen G.Y. (1985) Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann. Neurol. 17:278–282.[CrossRef][Web of Science][Medline]
60. Mann D.M., Yates P.O., Marcyniuk B., Ravindra C.R. (1986) The topography of plaques and tangles in Down's syndrome patients of different ages. Neuropathol. Appl. Neurobiol. 12:447–457.[Web of Science][Medline]
61. Mann D.M. and Esiri M.M. (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J. Neurol. Sci. 89:169–179.[CrossRef][Web of Science][Medline]
62. Lewis J., Dickson D.W., Lin W.L., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491.
63. Bales K.R., Verina T., Dodel R.C., et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17:263–264.[Web of Science][Medline]
64. Terry R.D. (1996) The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J. Neuropathol Exp. Neurol. 55:1023–1025.[Web of Science][Medline]
65. Irizarry M.C., Soriano F., McNamara M., Page K.J., Schenk D., Games D., Hyman B.T. (1997) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17:7053–7059.
66. Crook R., Verkkoniemi A., Perez-Tur J., et al. (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat. Med. 4:452–455.[CrossRef][Web of Science][Medline]
67. Houlden H., Baker M., McGowan E., et al. (2000) Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann. Neurol. 48:806–808.[CrossRef][Web of Science][Medline]
68. Braak H. and Del Tredici K. (2004) Alzheimer's disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol. Aging 25:713–718 discussion 743–746.[CrossRef][Web of Science][Medline]
69. Braak H. and Braak E3. (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18:351–357.[CrossRef][Web of Science][Medline]
70. Price J.L. and Morris J.C. (2004) So what if tangles precede plaques? Neurobiol. Aging 25:721–723.[CrossRef][Web of Science][Medline]
71. Morris J.C., Storandt M., McKeel D.W. Jr, Rubin E.H., Price J.L., Grant E.A., Berg L. (1996) Cerebral amyloid deposition and diffuse plaques in ‘normal’ aging: Evidence for presymptomatic and very mild Alzheimer's disease. Neurology 46:707–719.
72. Silverman W., Wisniewski H.M., Bobinski M., Wegiel J. (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18:377–9 Discussion 389–392.[CrossRef][Web of Science][Medline]
73. Price J.L. (1994) Tangles and plaques in healthy aging and Alzheimer's disease. Independence or interaction? Semin. Neurosci. 6:395–402.[CrossRef]
74. Nishimura M., Yu G., St George-Hyslop P.H. (1999) Biology of presenilins as causative molecules for Alzheimer disease. Clin. Genet. 55:219–225.[CrossRef][Web of Science][Medline]
75. Hardy J. (2001) The genetic causes of neurodegenerative diseases. J. Alzheimer's Dis. 3:109–116.[Medline]
76. Suzuki N., Cheung T.T., Cai X.D., Odaka A., Otvos L. Jr, Eckman C., Golde T.E., Younkin S.G. (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264:1336–1340.
77. Theuns J., Del-Favero J., Dermaut B., van Duijn C.M., Backhovens H., Van den Broeck M.V., Serneels S., Corsmit E., Van Broeckhoven C.V., Cruts M. (2000) Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. Hum. Mol. Genet. 9:325–331.
78. Wragg M., Hutton M., Talbot C. (1996) Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group. Lancet 347:509–512.[CrossRef][Web of Science][Medline]
79. Roses A.D. (1997) A model for susceptibility polymorphisms for complex diseases:apolipoprotein E and Alzheimer's disease. Neurogenetics 1:3–11.[CrossRef][Web of Science][Medline]
80. Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–923.
81. Dodel R.C., Du Y., Bales K.R., et al. (2000) Alpha2 macroglobulin and the risk of Alzheimer's disease. Neurology 54:438–442.
82. Blacker D., Wilcox M.A., Laird N.M., et al. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat. Genet. 19:357–360.[CrossRef][Web of Science][Medline]
83. Bertram L., Blacker D., Mullin K., et al. (2000) Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 290:2302–2303.
84. Ertekin-Taner N., Graff-Radford N., Younkin L.H., Eckman C., Baker M., Adamson J., Ronald J., Blangero J., Hutton M., Younkin S.G. (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science 290:2303–2304.
85. Takehashi M., Tanaka S., Masliah E., Ueda K. (2002) Association of monoamine oxidase A gene polymorphism with Alzheimer's disease and Lewy body variant. Neurosci. Lett. 327:79–82.[CrossRef][Web of Science][Medline]
86. Combarros O., Infante J., Llorca J., Pena N., Fernandez-Viadero C., Berciano J. (2002) The myeloperoxidase gene in Alzheimer's disease: a case–control study and meta-analysis. Neurosci. Lett. 326:33–36.[CrossRef][Web of Science][Medline]
87. Crawford F.C., Freeman M.J., Schinka J.A., Morris M.D., Abdullah L.I., Richards D., Sevush S., Duara R., Mullan M.J. (2001) Association between Alzheimer's disease and a functional polymorphism in the myeloperoxidase gene. Exp. Neurol. 167:456–459.[CrossRef][Web of Science][Medline]
88. Byrne U., Waldvogel H., Dragunow M., Kettle A., Faull R. (1999) Myeloperoxidase expression in Alzheimer's disease. Exp. Neurol. 155:31–41.[CrossRef][Web of Science][Medline]
89. Tanahashi H., Asada T., Tabira T. (2004) Association between tau polymorphism and male early-onset Alzheimer's disease. Neuroreport 15:175–179.[CrossRef][Web of Science][Medline]
90. Bullido M.J., Aldudo J., Frank A., Coria F., Avila J., Valdivieso F. (2000) A polymorphism in the tau gene associated with risk for Alzheimer's disease. Neurosci. Lett. 278:49–52.[CrossRef][Web of Science][Medline]
91. Mace S., Cousin E., Ricard S., et al. (2005) ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease. Neurobiol. Dis. 18:119–125.[CrossRef][Web of Science][Medline]
92. Licastro F., Chiappelli M., Grimaldi L.M., et al. (2005) A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease. Neurobiol. Aging 26:449–453.[CrossRef][Web of Science][Medline]
93. Bertram L., Hiltunen M., Parkinson M., et al. (2005) Family-based association between Alzheimer's disease and variants in UBQLN1. N. Engl. J. Med 352:884–894.
94. Mah A.L., Perry G., Smith M.A., Monteiro M.J. (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J. Cell. Biol. 151:847–862.
95. Baker M., Mackenzie I.R., Pickering-Brown S.M., et al. (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919.[CrossRef][Medline]
96. Petrozzi L., Lucetti C., Scarpato R., Gambaccini G., Trippi F., Bernardini S., Del Dotto P., Migliore L., Bonuccelli U. (2002) Cytogenetic alterations in lymphocytes of Alzheimer's disease and Parkinson's disease patients. Neurol. Sci. 23:Suppl. 2, S97–S98.
97. Migliore L., Testa A., Scarpato R., Pavese N., Petrozzi L., Bonuccelli U. (1997) Spontaneous and induced aneuploidy in peripheral blood lymphocytes of patients with Alzheimer's disease. Hum. Genet. 101:299–305.[CrossRef][Web of Science][Medline]
98. migliore l., Botto N., Scarpato R., Petrozzi I., Cipriani G., Bonuccelli U. (1999) Preferencial occurence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients. Cytogenet. Cell. Genet. 87:41–46.[CrossRef][Web of Science][Medline]
99. Geller L.N. and Potter H. (1999) Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease. Neurobiol. Dis. 6:167–179.[CrossRef][Web of Science][Medline]
100. Potter H. (1991) Review and hypothesis: Alzheimer disease and Down syndrome—chromosome 21 nondisjunction may underlie both disorders. Am. J. Hum. Genet. 48:1192–200.[Web of Science][Medline]
101. Wisniewski H.M., Rabe A., Wisniewski K.E. (1988) Neuropathology and dementia in People with Down's syndrome(Cold spring harbour Laboratory Press, New York).
102. Teller J.K., Russo C., DeBusk L.M., et al. (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome. Nat. Med. 2:93–95.[CrossRef][Web of Science][Medline]
103. Wang X., Thomas P., Xue J., Fenech M. (2004) Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21. Mutat. Res. 551:167–180.[Web of Science][Medline]
104. Schellenberg G.D., Bird T.D., Wijsman E.M., et al. (1992) Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258:668–671.
105. Sherrington R., Rogaev E.I., Liang Y., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–760.[CrossRef][Medline]
106. Li J., Xu M., Zhou H., Ma J., Potter H. (1997) Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 90:917–927.[CrossRef][Web of Science][Medline]
107. Deng G., Pike C.J., Cotman C.W. (1996) Alzheimer-associated presenilin-2 confers increased sensitivity to apoptosis in PC12 cells. FEBS. Lett. 397:50–54.[CrossRef][Web of Science][Medline]
108. Wisniewski T., Ghiso J., Frangione B. (1997) Biology of A beta amyloid in Alzheimer's disease. Neurobiol. Dis. 4:313–328.[CrossRef][Web of Science][Medline]
109. Das S. and Potter H. (1995) Expression of the Alzheimer amyloid promoting factor antichymotrypsin is induced in human astrocytes by IL-1. Neuron 14:447–456.[CrossRef][Web of Science][Medline]
110. Ramirez M.J., Puerto S., Galofre P., Parry E.M., Parry J.M., Creus A., Marcos R., Surralles J. (2000) Multicolour FISH detection of radioactive iodine-induced 17cen-p53 chromosomal breakage in buccal cells from therapeutically exposed patients. Carcinogenesis 21:1581–1586.
111. Surralles J., Hande M.P., Marcos R., Lansdorp P.M. (1999) Accelerated telomere shortening in the human inactive X chromosome. Am. J. Hum. Genet. 65:1617–1622.[CrossRef][Web of Science][Medline]
112. Panossian L.A., Porter V.R., Valenzuela H.F., Zhu X., Reback E., Masterman D., Cummings J.L., Effros R.B. (2003) Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol. Aging 24:77–84.[CrossRef][Web of Science][Medline]
113. Rufer N., Brummendorf T.H., Kolvraa S., Bischoff C., Christensen K., Wadsworth L., Schulzer M., Lansdorp P.M. (1999) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190:157–167.
114. Wu X., Amos C.I., Zhu Y., Zhao H., Grossman B.H., Shay J.W., Luo S., Hong W.K., Spitz M.R. (2003) Telomere dysfunction: a potential cancer predisposition factor. J. Natl Cancer Inst. 95:1211–1218.
115. Cawthon R.M., Smith K.R., O'Brien E., Sivatchenko A., Kerber R.A. (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361:393–395.[CrossRef][Web of Science][Medline]
116. Thomas von Zglinicki V.S., lorenz M., Saretzki G., Lenzen-grobimlighaus R., Gebner R., Risch A., Steinhagen-Thiessen E. (2000) Short telomeres in parients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor ? Lab. Invest. 80:1739–1747.[Web of Science][Medline]
117. Pennaneach V. and Kolodner R.D. (2004) Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast. Nat. Genet. 36:612–617.[CrossRef][Web of Science][Medline]
118. Shore D. (1998) Cell biology: enhanced telomeres—unsticky ends. Science 281:1818–1819.
119. Scheel C., Schaefer K.L., Jauch A., Keller M., Wai D., Brinkschmidt C., van Valen F., Boecker W., Dockhorn-Dworniczak B., Poremba C. (2001) Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene 20:3835–3844.[CrossRef][Web of Science][Medline]
120. Fenech M. and Crott J.W. (2002) Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes-evidence for breakage-fusion-bridge cycles in the cytokinesis-block micronucleus assay. Mutat. Res 504:131–136.[Web of Science][Medline]
121. McClintock B. (1941) Spotaneous alterations in chromosome size and form in Zea mays. Cold spring Harb. Sym. quant. Biol. 8:72–81.
122. Martens U., Zijlmans M,J,M, Poon S., dragowska W., Yui J., Chavez E.A, Ward R.K., Lansdorp P.M. (1998) Short telomeres on human chromosome 17p. Nat. Genet. 18:76–80.[CrossRef][Web of Science][Medline]
123. Lo A.W., Sabatier L., Fouladi B., Pottier G., Ricoul M., Murnane J.P. (2002) DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4:531–538.[CrossRef][Web of Science][Medline]
124. Leach N.T., Rehder C., Jensen K., Holt S., Jackson-Cook C. (2004) Human chromosomes with shorter telomeres and large heterochromatin regions have a higher frequency of acquired somatic cell aneuploidy. Mech. Ageing Dev 125:563–573.[CrossRef][Web of Science][Medline]
125. Maser R.S. and DePinho R.A. (2002) Connecting chromosomes, crisis, and cancer. Science 297:565–569.
126. Zglinicki T.V. (2002) Oxidative stress shorrtens telomeres. Trends Biochem. Sci. 27:339–344.[CrossRef][Web of Science][Medline]
127. Gabbita S.P., Lovell M.A., Markesbery W.R. (1998) Increased nuclear DNA oxidation in the brain in Alzheimer's disease. J. Neurochem. 71:2034–2040.[Web of Science][Medline]
128. Lovell M.A., Gabbita S.P., Markesbery W.R. (1999) Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF. J. Neurochem. 72:771–776.[CrossRef][Web of Science][Medline]
129. Mecocci P., Polidori M.C., Ingegni T., Cherubini A., Chionne F., Cecchetti R., Senin U. (1998) Oxidative damage to DNA in lymphocytes from AD patients. Neurology 51:1014–1017.
130. Smith M.A., Rudnicka-Nawrot M., Richey P.L., Praprotnik D., Mulvihill P., Miller C.A., Sayre L.M., Perry G. (1995) Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J. Neurochem. 64:2660–2666.[Web of Science][Medline]
131. Miyata M. and Smith J.D. (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 14:55–61.[CrossRef][Web of Science][Medline]
132. Poirier J. (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 17:525–530.[CrossRef][Web of Science][Medline]
133. Ramasamy K., Krzywokowski P., Bastianetto S. (1998) Apolipoprotein E, oxidative stress and EGb 761 in Alzheimer's disease brain. In Packer L. and Christen Y. (Eds.). Ginkgo Biloba Extract (egb 761) Study: Lessson from Cell Biology.(Elsevier, Paris) pp. 69–83.
134. Migliore L., Fontana I., Trippi F., Colognato R., Coppede F., Tognoni G., Nucciarone B., Siciliano G. (2005) Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol. Aging 26:567–573.[CrossRef][Web of Science][Medline]
135. Flint Beal M. (2005) Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment. Neurobiol. Aging 26:585–586.[CrossRef][Web of Science][Medline]
136. Mecocci P., Polidori M.C., Cherubini A., et al. (2002) Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch. Neurol. 59:794–798.
137. Nunomura A., Perry G., Aliev G., et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60:759–767.[Web of Science][Medline]
138. Aisen P.S., Egelko S., Andrews H., et al. (2003) A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease. Am. J. Geriatr. Psychiatr. 11:246–249.
139. Shea T.B. and Rogers E. (2002) Homocysteine and dementia. N. Engl. J. Med 346:2007 author reply 2008.
140. Scarpa S., Fuso A., D'Anselmi F., Cavallaro R.A. (2003) Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS Lett. 541:145–148.[CrossRef][Web of Science][Medline]
141. Suzuki T., Fujii M., Ayusawa D. (2002) Demethylation of classical satellite 2 and 3 DNA with chromosomal instability in senescent human fibroblasts. Exp. Gerontol. 37:1005–1014.[CrossRef][Web of Science][Medline]
142. Fenech M. (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat. Res. 475:57–67.[Web of Science][Medline]
143. Zingg J.M. and Jones P.A. (1997) Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis. Carcinogenesis 18:869–882.
144. Clarke R., Smith A.D., Jobst K.A., Refsum H., Sutton L., Ueland P.M. (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch. Neurol. 55:1449–1455.
145. Morris M.S. (2003) Homocysteine and Alzheimer's disease. Lancet Neurol. 2:425–428.[CrossRef][Web of Science][Medline]
146. Seshadri S., Beiser A., Selhub J., Jacques P.F., Rosenberg I.H., D'Agostino R.B., Wilson P.W., Wolf P.A. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 346:476–483.
147. Wang H.X., Wahlin A., Basun H., Fastbom J., Winblad B., Fratiglioni L. (2001) Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 56:1188–1194.
148. McCaddon A., Davies G., Hudson P., Tandy S., Cattell H. (1998) Total serum homocysteine in senile dementia of Alzheimer type. Int. J. Geriatr. Psychiatr. 13:235–239.[CrossRef][Web of Science][Medline]
149. Kruman H. II, Kumaravel T.S., Lohani A., Pedersen W.A., Cutler R.G., Kruman Y., Haughey N., Lee J., Evans M., Mattson M.P. (2002) Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J. Neurosci. 22:1752–1762.
150. Williams J.H., Pereira E.A., Budge M.M., Bradley K.M. (2002) Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing 31:440–444.
151. den Heijer T., Vermeer S.E., Clarke R. (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126:170–175.
152. Dwyer B.E., Raina A.K., Perry G., Smith M.A. (2004) Homocysteine and Alzheimer's disease: a modifiable risk? Free Radic. Biol. Med. 36:1471–1475.[CrossRef][Web of Science][Medline]
153. Mattson M.P. and Shea T.B. (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 26:137–146.[CrossRef][Web of Science][Medline]
154. Shea T.B., Lyons-Weiler J., Rogers E. (2002) Homocysteine, folate deprivation and Alzheimer neuropathology. J. Alzheimers. Dis. 4:261–267.[Medline]
155. Bunce D., Kivipelto M., Wahlin A. (2004) Utilization of cognitive support in episodic free recall as a function of apolipoprotein E and vitamin B12 or folate among adults aged 75 years and older. Neuropsychology 18:362–370.[CrossRef][Web of Science][Medline]
156. Morris M.C., Evans D.A., Bienias J.L., Scherr P.A., Tangney C.C., Hebert L.E., Bennett D.A., Wilson R.S., Aggarwal N. (2004) Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline. J. Neurol. Neurosurg. Psychiatr. 75:1093–1099.
157. Cohen-Armon M., Visochek L., Katzoff A., Levitan D., Susswein A.J., Klein R., Valbrun M., Schwartz J.H. (2004) Long-term memory requires polyADP-ribosylation. Science 304:1820–1822.
158. Qin W., Yang T., Ho L., et al. (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer's disease amyloid neuropathology by calorie restriction. J Biol Chem. 281:21745–21754.
159. James S.J., Pogribna M., Pogribny I.P., et al. (1999) Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am. J. Clin. Nutr. 70:495–501.
160. Frosst P., Blom H.J., Milos R., et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10:111–113.[CrossRef][Web of Science][Medline]
161. Lievers K.J., Boers G.H., Verhoef P., den Heijer M., Kluijtmans L.A., van der Put N.M., Trijbels F.J., Blom H.J. (2001) A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J. Mol. Med. 79:522–528.[CrossRef][Web of Science][Medline]
162. Brunelli T., Bagnoli S., Giusti B., Nacmias B., Pepe G., Sorbi S., Abbate R. (2001) The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease. Neurosci. Lett. 315:103–105.[CrossRef][Web of Science][Medline]
163. Wakutani Y., Kowa H., Kusumi M., Nakaso K., Yasui K., Isoe-Wada K., Yano H., Urakami K., Takeshima T., Nakashima K. (2004) A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease. Neurobiol. Aging 25:291–294.[CrossRef][Web of Science][Medline]
164. Beyer K., Lao J.I., Latorre P., Riutort N., Matute B., Fernandez-Figueras M.T., Mate J.L., Ariza A. (2003) Methionine synthase polymorphism is a risk factor for Alzheimer disease. Neuroreport 14:1391–1394.[CrossRef][Web of Science][Medline]
165. McCaddon A., Hudson P., Hill D., Barber J., Lloyd A., Davies G., Regland B. (2003) Alzheimer's disease and total plasma aminothiols. Biol. Psychiatr. 53:254–260.[CrossRef][Web of Science][Medline]
166. Morrison L.D., Smith D.D., Kish S.J. (1996) Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J. Neurochem 67:1328–1331.[Web of Science][Medline]
167. Abe K. and Kimura H. (1996) The possible role of hydrogen sulphide as an endogenous Neuromodulator. J. Neurosci. 16:1066–1071.
168. Eto K., Asada T., Arima K., Makifuchi T., Kimura H. (2002) Brain hydrogen sulphide is severely decreased in Alzheimer's disease. Biochem. Biophys. Res. Commun. 293:1485–1488.[CrossRef][Web of Science][Medline]
169. Kimura Y. and Kimura H. (2004) Hydrogen sulfide protects neurons from oxidative stress. FASEB J. 18:1165–1167.
170. Barbaux S., Plomin R., Whitehesd A. (2000) Polymorphisms of genes controlling honmocysteine/folate metabolism and cognitive function. Neuroreport 11:1133–1136.[Web of Science][Medline]
171. Payao S.L., Smith M.D., Bertolucci P.H. (1998) Differential chromosome sensitivity to 5-azacytidine in Alzheimer's disease. Gerontology 44:267–271.[CrossRef][Web of Science][Medline]
172. Andrea Fuso L.S., Cavallaro R., D'Anselmi F., Scarpa S. (2005) S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol. Cell. Neurosci. 28:195–204.[CrossRef][Web of Science][Medline]
173. West R.L., Lee J.M., Maroun L.E. (1995) Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. J. Mol. Neurosci. 6:141–146.[Web of Science][Medline]
174. Perry G., Raina A.K., Nunomura A., Wataya T., Sayre L.M., Smith M.A. (2000) How important is oxidative damage? Lessons from Alzheimer's disease. Free Radic. Biol. Med. 28:831–834.[CrossRef][Web of Science][Medline]
175. Perry G., Taddeo M.A., Nunomura A., Zhu X., Zenteno-Savin T., Drew K.L., Shimohama S., Avila J., Castellani R.J., Smith M.A. (2002) Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 133:507–513.[CrossRef][Web of Science][Medline]
176. Zandi P.P., Anthony J.C., Khachaturian A.S., Stone S.V., Gustafson D., Tschanz J.T., Norton M.C., Welsh-Bohmer K.A., Breitner J.C. (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch. Neurol. 61:82–88.
177. Rota C., Rimbach G., Minnihane A., Stocecklin E., Barella L. (2005) Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr. Neurosci. 8:21–29.[Web of Science][Medline]
178. Ringman J.M., Frautschy S.A., Cole G.M., Masterman D.L., Cummings J.L. (2005) A potential role of the curry spice curcumin in Alzheimer's disease. Curr. Alzheimer. Res. 2:131–136.[CrossRef][Medline]
179. Yang F., Lin G.P., Begum A.N., et al. (2005) curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 18:5892–901.
180. Ono K., Hasegawa K., Naiki H., Yamada M. (2005) Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem. Biophys. Res. Commun. 330:111–116.[CrossRef][Web of Science][Medline]
181. Baum L. and Ng A. (2004) Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J. Alzheimers. Dis. 6:367–377 Discussion 443–449.[Web of Science][Medline]
182. Wu X., Beecher G.R., Holden J.M., Haytowitz D.B., Gebhardt S.E., Prior R.L. (2004) Lipophilic and hydrophilic antioxidant capacities of common foods in the United States. J. Agric. Food Chem. 52:4026–4037.[CrossRef][Web of Science][Medline]
183. Joseph J.A., Denisova N.A., Arendash G., Gordon M., Diamond D., Shukitt-Hale B., Morgan D. (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr. Neurosci. 6:153–162.[CrossRef][Web of Science][Medline]
184. Joseph J.A., Shukitt-Hale B., Denisova N.A., Bielinski D., Martin A., McEwen J.J., Bickford P.C. (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci. 19:8114–8121.
185. Shi J., Yu J., Pohorly J.E., Kakuda Y. (2003) Polyphenolics in grape seeds-biochemistry and functionality. J. Med. Food 6:291–299.[CrossRef][Medline]
186. Li M.H., Jang J.H., Sun B., Surh Y.J. (2004) Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death. Ann. NY Acad. Sci. 1030:317–329.[CrossRef][Web of Science][Medline]
187. Deshane J., Chaves L., Sarikonda K.V., Isbell S., Wilson L., Kirk M., Grubbs C., Barnes S., Meleth S., Kim H. (2004) Proteomics analysis of rat brain protein modulations by grape seed extract. J. Agric. Food Chem. 52:7872–7883.[Web of Science][Medline]
188. Mandel S., Amit T., Reznichenko L., Weinreb O., Youdim M.B. (2006) Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol. Nutr. Food Res. 50:229–234.[CrossRef][Web of Science][Medline]
189. Rezai-Zadeh K., Shytle D., Sun N., et al. (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J. Neurosci. 25:8807–8814.
190. Okello E.J., Savelev S.U., Perry E.K. (2004) In vitro anti-beta-secretase and dual anti-cholinesterase activities of Camellia sinensis L. (tea) relevant to treatment of dementia. Phytother. Res. 18:624–627.[CrossRef][Web of Science][Medline]
191. Kuriyama S., Hozawa A., Ohmori K., Shimazu T., Matsui T., Ebihara S., Awata S., Nagatomi R., Arai H., Tsuji I. (2006) Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am. J. Clin. Nutr. 83:355–361.
192. Bush A.I. (2000) Metals and neuroscience. Curr. Opin. Chem. Biol. 4:184–191.[CrossRef][Web of Science][Medline]
193. Assaf S.Y. and Chung S.-H. (1984) Release of endogenous zinc from brain tissue. Nature 308:734–736.[CrossRef][Medline]
194. Bush A. and Tanzi R. (2002) The galavanization of b-amyloid in Alzheimer's disease. Proc. Natl Acad. Sci. USA 99:7317–7319.
195. Lovell M.A., Robertson J.D., Teesdale W.J., Campbell J.L., Markesbery W.R. (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158:47–52.[CrossRef][Web of Science][Medline]
196. Suh S.W., Jensen K.B., Jensen M.S., Silva D.S., Kesslak P.J., Danscher G., Frederickson C.J. (2000) Histochemically reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain. Res. 852:274–278.[CrossRef][Web of Science][Medline]
197. Atwood C.S., Moir R.D., Huang X., Scarpa R.C., Bacarra N.M., Romano D.M., Hartshorn M.A., Tanzi R.E., Bush A.I. (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 273:12817–12826.
198. Huang X., Atwood C.S., Hartshorn M.A., et al. (1999) The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38:7609–7616.[CrossRef][Medline]
199. Huang X., Cuajungco M.P., Atwood C.S., et al. (1999) Cu(II) potentiation of Alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 274:37111–37116.
200. Bush A.I. (2002) Metal complexing agents as therapies for Alzheimer's disease. Neurobiol. Aging 23:1031–1038.[CrossRef][Web of Science][Medline]
201. Cuajungco M.P., Goldstein L.E., Nunomura A., Smith M.A., Lim J.T., Atwood C.S., Huang X., Farrag Y.W., Perry G., Bush A.I. (2000) Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J. Biol. Chem. 275:19439–19442.
202. Lee J.Y., Mook-Jung I., Koh J.Y. (1999) Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice. J. Neurosci. 19:RC10.
203. Gonzalez S., Huerta J.M., Alvarez-Uria J., Fernandez S., Patterson A.M., Lasheras C. (2004) Serum selenium is associated with plasma homocysteine concentrations in elderly humans. J. Nutr. 134:1736–1740.
204. Perl D.P. and Brody A.R. (1980) Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 208:297–299.
205. Good P.F., Perl D.P., Bierer L.M., Schmeidler J. (1992) Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study. Ann. Neurol. 31:286–292.[CrossRef][Web of Science][Medline]
206. Duckett S., Galle P., Escourolle R., Grey F. (1976) [Presence of aluminum and magnesium in the cerebral arteries and parenchyma of patients with striatonigral syndrome: study by Castaing's microprobe]. C R Acad. Sci. Hebd. Seances Acad. Sci. D 282:2115–2117.[Medline]
207. Landsberg J.P., McDonald B., Watt F. (1992) Absence of aluminium in neuritic plaque cores in Alzheimer's disease. Nature 360:65–68.[CrossRef][Medline]
208. Neri L.C. and Hewitt D. (1991) Aluminium, Alzheimer's disease, and drinking water. Lancet 338:390.[Web of Science][Medline]
209. Flaten T.P. (2001) Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water. Brain. Res. Bull. 55:187–196.[CrossRef][Web of Science][Medline]
210. Bayley J. (1999) Elegy for Iris(St Martins, New york).
211. Wagner C. (1995) Biochemical Role of Folate in Cellular Metabolism. Folate in Health and Disease. Bailey L.B. (ed) pp. 26.
Received on August 11, 2006;
revised on October 18, 2006;
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