Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1 Delta E9 Mouse Model of Alzheimer's Disease

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer's disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (A beta). APPswe/PSdE1 (APP/PS1) mice display age-related A beta accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS(+/-) mice by crossing complete eNOS deficient (eNOS(-/-)) mice and APP/PS1 mice. APP/PS1/eNOS(+/-) mice at 8 months of age displayed a more severe spatial working memory deficit relative to age-matched APP/PS1 mice. Moreover, immunohistochemistry and immunoblotting revealed significantly increased A beta plaque load in the brains of APP/PS1/eNOS(+/-) mice, concomitant with upregulated BACE-1 (hence increased A beta production), downregulated insulin-degrading enzyme (hence reduced A beta clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, A beta brain deposition, and microglial pathology in APP/PS1 mice, further implicating endothelial dysfunction in the pathogenesis of AD. The present findings also provide the scientific basis for developing preventive and/or therapeutic strategies by targeting endothelial dysfunction.