Journal of Alzheimer’s Disease 4 (2002) 261–267 261 IOS Press Homocysteine, folate deprivation and Alzheimer neuropathology Thomas B. Shea, James Lyons-Weiler and Eugene Rogers Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, Department of Health and Clinical Sciences, Department of Biochemistry, UMass, Lowell, Lowell, MA 01854, USA Abstract. Increased levels of homocysteine (HC), arising in some situations via deficiencies in folate – an essential cofactor in metabolic regulation of HC – have long been known to contribute to cardiovascular disorders and stroke. More recently, clinical studies implicate increased HC and reduced folate with neurodegenerative conditions including Alzheimer’s disease. It has remained unclear from clinical studies whether the neurotoxicity of increased HC and/or reduced folate is derived from direct detrimental effects on neurons themselves, or is instead derived indirectly following perturbation of nervous system vasculature. However, recent reports from several laboratories provide evidence that HC not only induces direct neurotoxicity, but also potentiates both amyloid-beta and glutamate neurotoxicity. These latter studies leave open the possibility that even mild elevations in HC may place neurons at risk for additional trauma. The potential contribution of folate deficiency and resultant increases in HC to neurodegeneration in AD, and therapeutic approaches to alleviate their impact, is discussed. 1. Homocysteine and folate deprivation Homocysteine (HC), a non-protein amino acid re- versibly formed and secreted during metabolism, is a potent neurotoxin [39,43]. Elevated levels of HC are correlated with multiple neurological disor- ders, including Alzheimer’s disease (AD [10,21,49,50, 70]). Plasma HC has been reported to be elevated in some [10,35], but not all [17] confirmed cases of AD and represent an early marker of cognitive impairment in the elderly [41]. Major factors contributing to increased HC include deficiencies in folate and/or B12 [19]. Folate and B12 deficiency have long been implicated in cardiovascu- lar disorders, and only recently is it becoming appar- ent that they also contribute to many neurological and psychological disorders including dementia, impaired cognition, depression, psychosis and AD (e.g. [1,10, 16,25,67,83]. Significantly, it has been reported that low serum folate levels are strongly associated with at- rophy of the cerebral cortex [74]. In addition, while levels of folate in cerebral spinal fluid are normally 3 to 4-fold higher than in blood, spinal fluid levels of fo- late are significantly lower in AD patients [72]. High plasma HC is a consistent finding in these groups and reports continue to suggest the importance of folate in neuronal health [83]. The relationship between folate deficiency and HC accumulation is perhaps clarified by examination of the methionine metabolic cycle (Fig. 1). Methionine is normally converted to S-adenosyl- methionine (SAM) by adenosylation with adenosine triphosphate in a reaction catalyzed by methionine adenosyltransferase (e.g. [9]). SAM is required in sev- eral transmethylation reactions, including methylation of proteins, phospholipids, neurotransmitters and nu- cleic acids [54]. Transmethylation reactions involving SAM produce S-adenosylhomocysteine (SAH). SAH is then further hydrolyzed to HC via SAH hydrolase. Under normal conditions, HC is either (1) remethylated back to methionine via folate- and B12-dependent re- action or (2) converted to cystathionine by cystathion- ine β-synthase, which can lead to increased glutathione levels (e.g. [13]), in a possible compensatory mecha- nism to counteract the potential oxidative damage re- sulting from increased HC. Accordingly, one likely ma- jor impact of folate deprivation is increased HC pro- duction (e.g. [15]). A third fate for HC is extracellular transport, which increases when intracellular HC con- centrations become high due to inadequate vitamin lev- els, genetic enzyme deficiencies or excess methionine. ISSN 1387-2877/02/$8.00  2002 – IOS Press. All rights reserved