Speth, R. C. | bioRxiv Science

bioRxiv2025

Chronic Treatment of a Mouse Model of Cerebral Amyloid Angiopathy and Brain AT1 Receptor Expression

IntroductionThe 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 common cerebrovascular disease, currently has no treatment or cure available. We aimed to determine if a mouse model with CAA (Tg-SwDI) also exhibits elevated levels of AT1Rs and whether RAAS-targeting drugs (telmisartan and lisinopril) mitigate these effects. Materials and MethodsTg-SwDI mice were treated with sub-depressor doses of either telmisartan or lisinopril from 3-8 months of age, with blood pressure being monitored 2 and 4 months after the start of treatment. Postmortem, receptor autoradiography was performed to determine levels of AT1R in 13 brain regions in untreated and treated Tg-SwDI mice compared to wild-type controls (C57Bl/6J). ResultsNo statistically significant differences among groups were observed in any of the 13 regions analyzed. However, trends with medium to large effect sizes were observed. ConclusionsCAA did not significantly dysregulate AT1R levels in the brains of Tg-SwDI mice compared to wild-type mice. Drug treatment caused no significant brain AT1R alterations. Further studies are required to determine if the trends observed are pathophysiological and pharmacologically significant.

neuroscience↗

bioRxiv2025

Telmisartan and Lisinopril Show Potential Benefits in Rescuing Cognitive-Behavioral Function Despite Limited Improvements in Neuropathological Outcomes in Tg-SwDI Mice

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease that results from beta-amyloid (A{beta}) accumulation in the vessel walls that is associated with cognitive impairment and other neurological pathologies. There are currently no medications approved to treat CAA. This study investigated whether renin-angiotensin system (RAS)-targeting drugs, commonly prescribed to treat hypertension, can be repurposed to treat CAA, and whether their effects differ by sex. Male and female Tg-SwDI mice were treated for 5 months with sub-depressor doses of either telmisartan [angiotensin II receptor blocker (ARB)] or lisinopril [angiotensin-converting enzyme (ACE) inhibitor] starting at 3 months of age. Blood pressure monitoring was performed 2 and 4 months after the start of treatment, followed by behavior testing at 7 months of age. Histochemical analyses were conducted to determine vasculopathy, A{beta} pathology, and neuroinflammation (microgliosis and astrogliosis). Outcomes in drug-treated and untreated Tg-SwDI mice were compared to each other and with wild-type (C57BL/6J) controls. Overall, both drugs were able to rescue some cognitive-behavioral functions; however, no reductions in A{beta} levels were observed, and only limited improvements in vascular density and neuroinflammatory markers were detected. Notably, some treatment effects varied with sex, the specific behavioral task, and the brain region analyzed. These findings support the hypothesis that RAS-targeting drugs exert neuroprotective effects through mechanisms beyond blood pressure control offering a promising therapeutic avenue for CAA.

neuroscience↗