The central nervous system in animal models of hyperhomocysteinemia

Aron M. Troen*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

98 Scopus citations

Abstract

Growing epidemiological evidence of associations between mildly elevated plasma homocysteine with age-related cognitive impairment, neurodegenerative and cerebrovascular disease has stimulated interest in the role of homocysteine in neurological and neuropsychiatric disorders. Homocysteine is an intermediate in the folate, vitamin B12 and B6 dependent pathways of one-carbon and sulfur amino acid metabolism. Impairments of these pathways may cause CNS dysfunction by promoting the intracellular generation of homocysteine, which is postulated to have vasotoxic and neurotoxic properties. It might also inhibit the methylation of myelin basic protein and membrane phospholipids, or disrupt biogenic amine metabolism and many other vital CNS reactions. However, it is unclear which, if any, of these putative mechanisms underlies the epidemiological associations. Genetic mouse models of hyperhomocysteinemia suggest that the primary metabolic disturbances rather than homocysteine per se may be important in determining neurological outcomes. However, severe and early developmental abnormalities in these mice limit their usefulness for understanding the relation of hyperhomocysteinemia to adult CNS disorders. Pharmacologic and dietary studies on homocysteine in rodents have reported heightened neuronal sensitivity to neurotoxic insults, neurochemical abnormalities and cerebrovascular dysfunction. Such studies are consistent with a causal relationship, but they fail to distinguish between effects that might result from a dietary imbalance and those that might be caused by homocysteine per se. Future work should be directed towards refining these models in order to distinguish between the effects of homocysteine and its determinants on neurological and behavioral outcomes that represent different CNS disorders.

Original languageAmerican English
Pages (from-to)1140-1151
Number of pages12
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume29
Issue number7
DOIs
StatePublished - Sep 2005
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a grant from the Alzheimer's Association (NIRG-02-4119) and by the U.S. Department of Agriculture under cooperative agreement No.58-1950-9-001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.

Keywords

  • Alzheimer's disease
  • Animal models
  • Cerebrovascular disease
  • Dementia
  • Folate
  • Homocysteine
  • Methionine
  • Nutrition
  • Schizophrenia
  • Stroke

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