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Hyperhomocysteinemia in Alzheimer's disease: The hen and the egg?


Farkas, M; Keskitalo, S; Smith, D E C; Bain, N; Semmler, A; Ineichen, B; Smulders, Y; Blom, H; Kulic, L; Linnebank, M (2013). Hyperhomocysteinemia in Alzheimer's disease: The hen and the egg? Journal of Alzheimer's disease : JAD, 33(4):1097-1104.

Abstract

Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcA-beta transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcA-beta mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemia-inducing diet were lower in the transgenic than in the wild-type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcAβ mice, consumes 5-MTHF. Thus, the transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-β concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.

Abstract

Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcA-beta transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcA-beta mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemia-inducing diet were lower in the transgenic than in the wild-type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcAβ mice, consumes 5-MTHF. Thus, the transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-β concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:29 Nov 2012 11:06
Last Modified:07 Dec 2017 16:46
Publisher:IOS Press
Series Name:Journal of Alzheimer's Disease
ISSN:1387-2877
Publisher DOI:https://doi.org/10.3233/JAD-2012-121378
PubMed ID:23099812

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