Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease

Kruman, Inna I.; Kumaravel, T. S.; Lohani, Althaf; Pedersen, Ward A.; Cutler, Roy G.; Kruman, Yuri; Haughey, Norman J.; Lee, Jaewon; Evans, Michele K.; Mattson, Mark P.

doi:10.1523/jneurosci.22-05-01752.2002

Cited by 582 publications

(388 citation statements)

References 77 publications

(94 reference statements)

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“…For example, the same concentrations of DNA damaging agents that kill neurons do not kill astrocytes, i.e., the threshold is higher in proliferating cells. Doublestrand breaks are the most dangerous type of DNA damage, and the occurrence of this type of damage is much lower than 8-oxoguanine modification or single-strand breaks; 8-oxoguanine in neurons is associated with hereditary chronic disorders in animal models (Bogdanov et al 2000(Bogdanov et al , 2001Kruman et al 2002). While cell culture models provide clear evidence that cells will either undergo apoptosis if they cannot repair DNA after DNA damage or display dephosphorylated γH2AX following repair, the actual situation in vivo, especially in a chronic disease condition, is likely different than in a cell culture model system.…”

Section: Discussionmentioning

confidence: 99%

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Myung

Zhu

Kruman

et al. 2008

AGE

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143

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Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear.In an effort to clarify this, we investigated the expression of γH2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate γH2AX. Using immunocytochemical techniques, we found significantly increased levels of γH2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.

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Section: Discussionmentioning

confidence: 99%

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Myung

Zhu

Kruman

et al. 2008

AGE

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143

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“…51,53,54 Recently, experiments with mice have shown that these mechanisms are not only important in cultured embryonic premitotic neurons, but in the adult postmitotic neurons as well. 55 The deleterious effect of MTHFR dysfunction on brain development was observed in individuals with a severe deficiency of this enzyme, resulting in delayed psychomotor development, mental retardation and psychiatric symptoms. 56 The 70% higher risk of schizophrenia for a 5 mmol/l increase in homocysteine observed in our metaanalysis suggests a dose-response relationship.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

Muntjewerff¹,

et al. 2005

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Elevated plasma homocysteine concentration has been suggested as a risk factor for schizophrenia, but the results of epidemiological studies have been inconsistent. The most extensively studied genetic variant in the homocysteine metabolism is the 677C4T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, resulting in reduced enzyme activity and, subsequently, in elevated homocysteine. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) was carried out to examine the association between homocysteine and schizophrenia. In addition, a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C4T polymorphism was carried out to assess if this association is causal. A 5 lmol/l higher homocysteine level was associated with a 70% (95% confidence interval, CI: 27-129) higher risk of schizophrenia. The TT genotype was associated with a 36% (95% CI: 7-72) higher risk of schizophrenia compared to the CC genotype. The performed meta-analyses showed no evidence of publication bias or excessive influence attributable to any given study. In conclusion, our study provides evidence for an association of homocysteine with schizophrenia. The elevated risk of schizophrenia associated with the homozygous genotype of the MTHFR 677C4T polymorphism provides support for causality between a disturbed homocysteine metabolism and risk of schizophrenia.

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“…Homocysteine, however, has also been shown to be a risk factor in patients with neuropathologically confirmed AD without significant cerebrovascular disease or atherosclerosis [27]. More recent animal studies [40] provide evidence that folic acid deficiency and homocysteine may be directly related to amyloid toxicity by impairing DNA repair in neurons, which results in sensitization to oxidative damage induced by β-amyloid (a protein that is accumulated in excess in AD brains). This suggests a non-vascular mechanism by which folate intake may be related to the development of AD.…”

Section: Discussionmentioning

confidence: 99%

Reduced risk of Alzheimer's disease with high folate intake: The Baltimore Longitudinal Study of Aging

Corrada

Kawas

Hallfrisch

et al. 2005

Alzheimer's & Dementia

133

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Background-Study findings have suggested an association between Alzheimer's disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B 6 , and B 12 ) is associated with a reduced risk of AD.Methods-Participants were 579 nondemented elderly volunteers from the Baltimore Longitudinal Study of Aging who completed dietary diaries and recorded supplement intake for a 7-day period. Cox regression was used to estimate the relative risk (RR) of AD associated with total vitamin intake categorized into levels above or below the Recommended Dietary Allowance (RDA).Results-After a mean follow-up of 9.3 years, AD developed in 57 participants. Higher intake of folate (RR, 0.41; 95% confidence interval [CI], 0.22 to 0.76), vitamin E (RR, 0.56; 95% CI, 0.30 to 1.06), and vitamin B 6 (RR, 0.41; 95% CI, 0.20 to 0.84) were associated individually with a decreased risk of AD after adjusting for age, gender, education, and caloric intake. When these 3 vitamins were analyzed together, only total intake of folate at or above the RDA (RR, 0.45; 95% CI, 0.21 to 0.97) was associated with a significant decreased risk of AD. No association was found between total intake of vitamins C, carotenoids, or vitamin B 12 and risk of AD.Conclusions-These findings suggest that total intake of folate at or above the RDA is associated with a reduced risk of AD. Additional studies are necessary to further investigate whether folate or other(s) unmeasured factor(s) may be responsible for this reduction in risk.

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Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease

Cited by 582 publications

References 77 publications

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

Reduced risk of Alzheimer's disease with high folate intake: The Baltimore Longitudinal Study of Aging

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