| First Author | Ahmed S | Year | 2022 |
| Journal | Int J Mol Sci | Volume | 23 |
| Issue | 13 | PubMed ID | 35806318 |
| Mgi Jnum | J:326765 | Mgi Id | MGI:7313192 |
| Doi | 10.3390/ijms23137316 | Citation | Ahmed S, et al. (2022) Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1DeltaE9 Mouse Model of Alzheimer's Disease. Int J Mol Sci 23(13) |
| abstractText | 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 (Abeta). APPswe/PSdE1 (APP/PS1) mice display age-related Abeta 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 Abeta plaque load in the brains of APP/PS1/eNOS(+/-) mice, concomitant with upregulated BACE-1 (hence increased Abeta production), downregulated insulin-degrading enzyme (hence reduced Abeta clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, Abeta 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. |
