Endothelial nitric oxide deficiency promotes Alzheimer's disease pathology

Aging and the presence of cerebrovascular disease are associated with increased incidence of Alzheimer's disease. A common feature of aging and cerebrovascular disease is decreased endothelial nitric oxide (NO). We studied the effect of a loss of endothelium derived NO on amyloid precursor protein (APP) related phenotype in late middle aged (LMA) (14-15month) endothelial nitric oxide synthase deficient (eNOS(-/-)) mice. APP, -site APP cleaving enzyme (BACE) 1, and amyloid beta (A) levels were significantly higher in the brains of LMA eNOS(-/-) mice as compared with LMA wild-type controls. APP and A(1-40) were increased in hippocampal tissue of eNOS(-/-) mice as compared with wild-type mice. LMA eNOS(-/-) mice displayed an increased inflammatory phenotype as compared with LMA wild-type mice. Importantly, LMA eNOS(-/-) mice performed worse in a radial arm maze test of spatial learning and memory as compared with LMA wild-type mice. These data suggest that chronic loss of endothelial NO may be an important contributor to both A related pathology and cognitive decline.