Evaluating AT₁R expression and the effects of renin-angiotensin system inhibition in a mouse model of cerebral amyloid angiopathy

Introduction: The renin-angiotensin-aldosterone system (RAAS) has been shown to be dysregulated in dementia, with elevated levels of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptors (AT₁Rs). Cerebral amyloid angiopathy (CAA), a dementia-causing cerebrovascular disease, currently has no treatment or cure available. We assessed whether a mouse model with CAA (Tg-SwDI) exhibits elevated levels of AT₁Rs and whether RAAS-targeting drugs (telmisartan and lisinopril) affect these levels. Materials and methods: Tg-SwDI mice were treated with sub-depressor doses of either telmisartan or lisinopril from 3 to 8 months of age, with blood pressure being monitored 2 and 4 months after the start of treatment. Post-mortem, receptor autoradiography was performed to determine levels of AT₁R in 13 brain regions in untreated and treated Tg-SwDI mice compared to untreated wild-type controls (C57BL/6J mice). Results: No statistically significant differences among groups were observed in AT₁R levels in any of the 13 brain regions analyzed. Although sexual dimorphism in blood pressure was observed in both wild-type and Tg-SwDI mice (males > females), drug treatment did not significantly lower blood pressure in Tg-SwDI mice, confirming the delivery of sub-depressor doses. Conclusions: Regional brain AT₁R levels were not significantly dysregulated in Tg-SwDI mice compared to wild-type mice. Additionally, drug treatment with sub-depressor doses of the AT₁R antagonist, telmisartan, or the ACE inhibitor, lisinopril, caused no significant brain AT₁R alterations in Tg-SwDI mice. This suggests that pathophysiological changes in the brain renin-angiotensin system do not mediate the cognitive impairments and neuropathological changes associated with CAA in Tg-SwDI mice.