Vascular Disease, Parkinson's, and Now Alzheimer's—Is Homocysteine the New All-Around Bad Guy?
Mark Mattson led this live discussion on 30 April 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 29 August 2006View Comments By:
A. David Smith — Posted 12 May 2002
By Gabrielle Strobel
Now famous for having been overlooked since the 1960s as risk factor for heart disease, the amino acid homocysteine has in past few years become a suspect in neurodegenerative diseases, as well. Folate and vitamin B12 are required in the methylation of homocysteine to methionine, and extreme vitamin B12 deficiency has long been known to cause a dementia that is treatable with vitamin supplementation. Epidemiological research has implicated elevated levels of homocysteine in stroke (Ridker et al., 2000; Morris et al., 2000; Aronow et al., 2000), Alzheimer's (McCaddon et al, 1998), and, just this month, silent white matter infarcts (Vermeer et al. 2002).
But the relationship to dementia in general, and Alzheimer's in particular, has remained vague. There were negative studies as well as positive ones, (see for example Fallon et al., 2001). The correlation with Alzheimer's disease was weak (Breteler, 2000). Research on Parkinson's focused mostly on levodopa-induced increases of homocysteine, and no one knew precisely how this amino acid might promote neurodegenerative disease.
That's changing now. Two current studies have simultaneously strengthened the epidemiological evidence and advanced an intriguing cellular mechanism, providing ample fodder for a discussion (see ARF news story and comments). For one, the Framingham cohort has revealed a robust link between elevated homocysteine levels and increased risk of developing Alzheimer's. For another, a recent study from Mattson's lab (Kruman et al., 2000) began establishing a mechanism by showing that homocysteine increases hippocampal neurons' vulnerability to excitotoxic and oxidative injury in cell culture and in vivo. Mattson and Kruman's current paper (Kruman et al., 2002) enters amyloid into this scenario by suggesting that homocysteine makes hippocampal neurons particularly sensitive to Aβ-induced cell death, and that a diet low in folic acid promotes neurodegeneration in AβPP-transgenic mice.
The surprising twist in this amyloid connection is that homocysteine does not do its damage by increasing Ab production, as do the AbPP and presenilin mutations that underlie familial Alzheimer's disease. Rather, it impairs the neuron's ability to repair DNA damage. A gradual erosion of the cell's ability to repair DNA-damaged by reactive oxygen species and other assaults-has long been thought to be one mechanism of cellular aging. This raises the question whether homocysteine might be a player in neurodegenerative processes in general, acting via Aβ to exacerbate Alzheimer's and perhaps via different neurotoxins in other neurodegenerative diseases. Intriguingly, folate deficiency also worsens pathology in a mouse model of Parkinson's (Duan et al., 2002), though a molecular mechanism is unknown in this system.
Such data generate a sense of urgency about considering public health measures. Unlike other research implicating novel targets for which drugs must yet be developed, we could affect people's homocysteine levels via the food supply immediately.
Mark Mattson, who will lead the discussion, has posed the following questions for the online chat:
- What are the implications of the link between homocysteine and risk for AD and PD, and genetic factors that may promote or prevent AD and PD?
- What other epidemiological, clinical and basic research studies should be pursued to better clarify the role of homocysteine in neurodegenerative disorders?
- Beyond folic acid, what dietary factors influence homocysteine levels?
- What are the mechanisms whereby homocysteine promotes neuronal degeneration?
- What are the contributions of effects on the cerebral vasculature versus direct effects on neurons?
- What kinds of clinical trials should be done (primary prevention and treatment)?
- What are the implications for education of the general public as to steps they can take to reduce risk of AD and PD?
The Alzheimer Research Forum invites you to consider these questions and join the debate. We also welcome your comments and will post them in advance of the debate to stimulate further thought.
Comment from Thomas Shea—Posted 28 April 2002.
Shea and colleagues have demonstrated that folate and vitamin E can
compensate for the diminished oxidative buffering capacity of brains of
apolipoprotein E-deficient mice. Normal and ApoE homozygous "knockout"
mice were maintained for one month on a diet either lacking or
supplemented with folate, vitamin E or iron as a pro-oxidant, after
which brain tissue was harvested and analyzed for for thiobarbituric
acid-reactive substances (TBARs) as an index of oxidative damage.
Normal mice exhibited no significant difference in TBARs following iron
challenge in the presence or absence of vitamin E, folic acid or both.
Similarly, ApoE knockout mice exhibited no significant differences
following dietary iron challenge in the presence or absence of vitamin
However, ApoE knockout mice accumulated significantly increased
TBARs following iron challenge when folic acid was withheld, and
accumulated even more TBARs when both folic acid and vitamin E were
withheld. These findings demonstrate that ApoE knockout mice during
vitamin deficiency are less capable of buffering the consequences of
dietary iron challenge than are normal mice. Since the
apolipoprotein E4 allele, which exhibits diminished oxidative buffering
capacity, is linked to Alzheimer's disease (AD), these data underscore
the possibility that critical nutritional deficiencies may modulate the
impact of genetic compromise on neurodegeneration in AD.
Thomas B Shea, Ph.D.
Professor of Biological Sciences and Biochemistry
Director, Center for Cellular Neurobiology & Neurodegeneration Research
University of Massachusetts-Lowell
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