Submitted to: Journal of Alzheimer's Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/1/2006
Publication Date: 8/1/2006
Citation: Troen, A.M., Shukitt Hale, B., Chao, W., Alburquerque, B., Smith, D.E., Selhub, J., Rosenberg, I. 2006. The cognitive impact of nutritional homocysteinemia in apolipoprotein-E deficient mice. Journal of Alzheimer's Disease. 9(4): 381-92.
Interpretive Summary: Elevated blood concentrations of homocysteine, a sulfur containing amino acid, are associated with cognitive dysfunction in the elderly ranging from subtle cognitive decline to dementia. Homocysteine can accumulate in blood due to dietary deficiencies of folate and vitamins B12 and B6 or through excessive intake of the amino acid methionine. While each of these conditions may result in high blood homocysteine, it is uncertain whether this will also lead to cognitive dysfunction. Genetically engineered mice that are prone to vascular disease and brain degeneration were fed diets with different nutritional imbalances that caused homocysteine to increase. Homocysteine raising diets caused poor performance on a specific test of memory and learning and subtle chemical changes in brain without causing apparent degeneration to brain cells. The diets that caused these changes were different than those that enhanced damage to aorta. Our findings suggest that different nutritional imbalances that raise homocysteine levels may lead to different end organ dysfunctions and diseases.
Technical Abstract: Homocysteinemia is associated with cognitive dysfunction in the elderly ranging from subtle cognitive decline to dementia. Homocysteine is generated from methionine as a product of biological methylation reactions and is disposed of through reactions that require folate and vitamins B12 and B6. While different disruptions in these reactions can result in homocysteinemia, it is unclear if they will also result in homocysteine-mediated cognitive dysfunction. Young ApoE-deficient mice were fed one of four diets with differing methionine and B-vitamin content for eight weeks, before undergoing psychomotor tests, the Morris Water Maze test of spatial memory and learning, and measurement of home-cage activity. B-vitamin deficiency induced homocysteinemia and selectively impaired Morris Water Maze performance without affecting other behavioral measures. The cognitive deficits occurred in the absence of overt histologic neurodegeneration but in association with moderate impairments of brain methylation potential. Diets that yielded cognitive deficits were different from those that exacerbated aortic pathology. These findings are inconsistent with a single mechanism linking homocysteinemia to neurological dysfunctions mediated by homocysteine vasotoxicity. Instead, they indicate that different “types” of homocysteinemia, or in other words different impairments of nutritional metabolism affecting homocysteine levels, may lead to different end organ dysfunctions and diseases.