TY - JOUR
T1 - B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice
AU - Troen, Aron M.
AU - Shea-Budgel, Melissa
AU - Shukitt-Hale, Barbara
AU - Smith, Donald E.
AU - Selhub, Jacob
AU - Rosenberg, Irwin H.
PY - 2008/8/26
Y1 - 2008/8/26
N2 - In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r = -0.757, P < 0.001), and with plasma total homocysteine (r = -0.631, P = 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.
AB - In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r = -0.757, P < 0.001), and with plasma total homocysteine (r = -0.631, P = 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.
KW - Cerebrovascular
KW - Homocysteine
KW - Mouse
KW - Nutrition
UR - http://www.scopus.com/inward/record.url?scp=50449105289&partnerID=8YFLogxK
U2 - 10.1073/pnas.0805350105
DO - 10.1073/pnas.0805350105
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C2 - 18711131
AN - SCOPUS:50449105289
SN - 0027-8424
VL - 105
SP - 12474
EP - 12479
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 34
ER -