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Homocysteine, folate deprivation and Alzheimer neuropathology
Thomas B Shea1, James Lyons-Weiler, Eugene Rogers
1Center 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.
Insights
Elevated homocysteine (HC) and low folate are linked to neurodegeneration, including Alzheimer's disease. Research shows HC directly harms neurons and worsens other toxic effects, highlighting risks even from mild HC increases.
Area of Science:
- Neuroscience
- Biochemistry
- Cardiovascular Medicine
Background:
- Elevated homocysteine (HC) is linked to cardiovascular disorders, stroke, and neurodegenerative diseases like Alzheimer's disease (AD).
- The role of folate, an essential cofactor in homocysteine metabolism, is critical in understanding these conditions.
- It remains unclear if neurotoxicity from HC and folate deficiency is direct or indirect via vascular damage.
Purpose of the Study:
- To investigate the direct neurotoxic effects of elevated homocysteine.
- To examine the potentiation of amyloid-beta and glutamate neurotoxicity by homocysteine.
- To discuss the contribution of folate deficiency and HC to neurodegeneration in AD and potential therapeutic strategies.
Main Methods:
- Review of recent laboratory findings and clinical studies.
- Analysis of homocysteine's direct impact on neuronal cells.
- Assessment of homocysteine's interaction with amyloid-beta and glutamate pathways.
Main Results:
- Homocysteine induces direct neurotoxicity.
- Homocysteine potentiates both amyloid-beta and glutamate-induced neurotoxicity.
- Even mild elevations in homocysteine may increase neuronal vulnerability.
Conclusions:
- Homocysteine exerts direct detrimental effects on neurons.
- Folate deficiency and resulting hyperhomocysteinemia contribute to neurodegeneration in AD.
- Therapeutic strategies targeting folate levels and homocysteine may mitigate neurodegenerative processes.
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.