Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine

Authors: TROEN, ARON - TUFTS UNIVERSITY; CHAO, WEI-HSUN - TUFTS UNIVERSITY; CRIVELLO, NATALIA - TUFTS UNIVERSITY; Shukitt-Hale, Barbara; Smith, Donald; Selhub, Jacob; Rosenberg, Irwin

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2008
Publication Date: 12/1/2008
Citation: Troen, A.M., Chao, W., Crivello, N.A., Shukitt Hale, B., Smith, D., Selhub, J., Rosenberg, I. 2008. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine. Journal of Nutrition. 138(12):2502-2509.

Interpretive Summary: Older adults with insufficient intake of folate (a B-vitamin) may be at higher risk of cognitive decline and dementia, as compared to individuals with adequate folate levels. However, it is unclear how folate deficiency impairs cognition. To better understand how folate deficiency might cause cognitive impairment, we fed rats folate deficient diets with or without additional methionine (an important amino which is conserved by the body with the help of folate or lost by the body if folate is insufficient). Rats fed the folate deficient diet without added methionine performed more poorly on a test of memory and learning than rats fed the folate deficient diet with added methionine. However, this impairment was prevented by adding methionine to the folate-deficient diet. Indeed, rats fed the folate-deficient diet with added methionine performed as well on the test of memory and learning as rats fed a control diet containing adequate folate and normal methionine. The cognitive impairment that was caused by folate deficiency corresponded to a reduction in the content of phosphatidylcholine (a fatty component of cell membranes), and adding methionine to the folate deficient diet this reduction. Our findings provide evidence that one way in which folate deficiency might harm the brain is by limiting the brain’s supply of methionine and/or phosphatidylcholine. Phosphatidylcholine and its related choline compounds are important nutrients, and they can be used to produce the brain signaling molecule acetylcholine. Our findings indicate that maintaining adequate dietary intake of folate and choline is important for healthy brain function.

Technical Abstract: Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely believed to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate deficient diets with or without supplemental methionine for 10 weeks, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, and this finding was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain SAM and SAH concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate-related cognitive dysfunction.