Journal
NEUROBIOLOGY OF DISEASE
Volume 134, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.104644
Keywords
Memory; erebrovascular function; AT4R; Renin angiotensin system
Categories
Funding
- Canadian Institutes of Health Research [MOP -126001]
- Heart and Stroke Foundation of Canada
- Canadian Vascular Network-Hypertension
- Fonds de Recherche du Quebec-Sante
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Angiotensin II type 1 receptor antagonists like losartan have been found to lower the incidence and progression to Alzheimer's disease (AD), as well as rescue cognitive and cerebrovascular deficits in AD mouse models. We previously found that co-administration of an angiotensin IV (AngIV) receptor (AT4R) antagonist prevented losartan's benefits, identifying AT4Rs as a possible target to counter AD pathogenesis. Therein, we investigated whether directly targeting AT4Rs could counter AD pathogenesis in a well-characterized mouse model of AD. Wild-type and human amyloid precursor protein (APP) transgenic (J20 line) mice (4.5 months old) received vehicle or AngIV (similar to 1.3 nmol/day, 1 month) intracerebroventricularly via osmotic minipumps. AngIV restored short-term memory, spatial learning and memory in APP mice. AngIV normalized hippocampal AT4R levels, increased hippocampal subgranular zone cellular proliferation and dendritic arborization, and reduced oxidative stress. AngIV rescued whisker-evoked neurovascular coupling, endothelial- and smooth muscle cell-mediated cerebral vasodilatory responses, and cerebrovascular nitric oxide bioavailability. AngIV did not alter blood pressure, neuroinflammation or amyloid-beta (A beta) pathology. These preclinical findings identify AT4R as a promising target to counter A beta-related cognitive and cerebrovascular deficits in AD.
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