Homocysteine and Alzheimer's disease: a modifiable risk?

doi:10.1016/j.freeradbiomed.2004.03.009

Free Radical Biology and Medicine

Volume 36, Issue 11, 1 June 2004, Pages 1471-1475

https://doi.org/10.1016/j.freeradbiomed.2004.03.009 Get rights and content

Abstract

A hypothesis is proposed that reconciles the epidemiological observation of elevated homocysteine in Alzheimer's disease (AD) with clinical features of the disease, particularly evidence of increased oxidative stress. We propose homocysteine is involved in an iron dysregulation/oxidative stress cycle that has a central role in the pathogenesis of AD. The implications of the hypothesis and some strategies for testing it are discussed.

Introduction

A recent article reported that elevated plasma homocysteine is a strong, independent risk factor for the development of Alzheimer's disease (AD) [1], but did not shed light on any relevant mechanism(s). Elevated plasma homocysteine implies impaired cellular clearance of homocysteine and elevated brain homocysteine has been reported in AD [2]. Furthermore, hydrogen sulfide (H₂S), a neuromodulator, produced in response to neuronal excitation [3] is severely reduced in AD [2]. Both observations are explained by reduced activity of the enzyme cystathionine β-synthase (EC 4.2.1.22) (CβS), which is one of two available routes of neuronal homocysteine metabolism, and the source of H₂S in brain.

Section snippets

General considerations

Homocysteine is a key metabolic intermediate in sulfur amino acid metabolism [4]. Briefly, homocysteine is remethylated to methionine by 5-methyltetrahydrofolate–homocysteine S-methyltransferase (EC 2.1.1.13), which is a 5-methyltetrahydrofolate- and vitamin B₁₂-dependent pathway, and by betaine–homocysteine S-methyltransferase (EC 2.1.1.5), which is part of a mitochondrial choline-degrading pathway. The former is active in brain and the latter is not. Homocysteine is also catabolized via the

CβS function in brain

What is the function of CβS in brain? As stated above, CβS catalyzes the condensation reaction of homocysteine and l-serine, which forms cystathionine. We surmise that CβS takes on increased importance for homocysteine homeostasis in brain tissue when homocysteine methylation via methyltetrahydrofolate-homocysteine S-methyltransferase is impaired, in folate deficiency, for example. Efflux from neurons would reduce neuronal homocysteine but risks excitotoxicity [6]. By a different reaction

Hypothesis

We hypothesize that reduced CβS activity and elevated homocysteine (perhaps secondary to heme deficiency) may be part of a vicious circle, involving iron regulation and oxidative stress, which contributes to the early oxidative pathophysiology that is seen in AD brain. A model of AD progression, which emphasizes the primacy of these early metabolic changes in AD brain, is shown in Fig. 1.

Homocysteine mobilizes storage iron from ferritin in vitro [11]. Moreover, sulfhydryl compounds, like

Testing the hypothesis

Mutations in the CβS gene are relatively common and obligate heterozygotes can have significantly reduced CβS activity [4]. Moreover, a significant number of CβS heterozygotes may also be heterozygous for other AD-related genes. Thus, hemochromatosis is the most common inherited monogenic disease of people of European descent [21]. The HFE gene regulates iron homeostasis, and a mutation in the HFE gene was reported to affect the age of onset of sporadic AD [21]. In this regard it may be of

Conclusions

Elevated homocysteine may be part of a vicious circle involving iron regulation and oxidative stress that could account for a majority of the early events seen in AD. The early stage of AD may be a critical period in disease progression during which affected neurons undergo adaptive change and switch from a functional mode to a survival mode of existence [23]. It may also be the critical stage of AD as far as therapeutic intervention is concerned [23]. Our proposed model is consistent with the

Broader implications

Variations in the ferric cycle shown in Fig. 1 may be relevant in other diseases. Of particular interest, the CβS gene is localized on chromosome 21, the locus of several familial AD pedigrees as well as being trisomic in Down syndrome. In Down syndrome, both CβS gene dosage and CβS activity are increased [28]. In contrast to AD, increased generation of H₂S in brain has been postulated as a mechanism of cognitive dysfunction in Down syndrome [29]. Also in contrast to AD, homocysteine is reduced

Acknowledgements

This work was supported by the Medical Research Service of the Department of Veterans Affairs (B.E.D.) and by the National Institutes of Health and the Alzheimer's Association (A.K.R., G.P., M.A.S.). None of the sponsors, however, had any direct involvement with this work. The authors also acknowledge Dr. Peter Sinclair (VAM&ROC, White River Junction, VT, and Dartmouth Medical School) and Dr. Glenn Gerhard (presently at the Weis Center for Research, Geisinger Clinic, Danville, PA) for many

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The role of oxidative stress in AD is documented by various animal experiments which revealed that oxidative stress markers such as lipid peroxidation precede Aβ pathology. It has been reported that homocysteine, a non-protein amino acid, is important in AD [69]; because AD patients exhibit increased concentrations of homocysteine in plasma and serum, this might be thus considered as a potential blood biomarker of AD. In addition, it has been demonstrated that a tight interaction of homocysteine with iron together with increased protein carbonylation is a prerequisite for oxidative damage to occur.
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¹: B.E.D. and M.A.S. developed the initial hypothesis, and thereafter all authors contributed equally to this work.

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Hypothesis PaperHomocysteine and Alzheimer's disease: a modifiable risk?

Abstract

Introduction

Section snippets

General considerations

CβS function in brain

Hypothesis

Testing the hypothesis

Conclusions

Broader implications

Acknowledgements

Biochem. Biophys. Res. Commun

Biochim. Biophys. Acta

J. Biol. Chem

Arch. Biochem. Biophys

J. Inorg. Biochem

Neurobiol. Aging

Comp. Biochem. Physiol. C

J. Biol. Chem

Am. J. Hum. Genet

Biochem. Biophys. Res. Commun

Med. Hypoth

Free Radic. Biol. Med

Biochem. Biophys. Res. Commun

Biophys. Chem

Plasma homocysteine as a risk factor for dementia and Alzheimer's disease

N. Engl. J. Med

Hydrogen sulfide is produced in response to neuronal excitation

J. Neurosci

Hypothesis Paper
Homocysteine and Alzheimer's disease: a modifiable risk?