Effects of Renin-Angiotensin System Targeting Drugs on Cerebral Amyloid Angiopathy and Related Neuropathology

Effects of Renin-Angiotensin System Targeting Drugs on Cerebral Amyloid Angiopathy and Related Neuropathology

Alvin Sherman Library

Cerebral amyloid angiopathy (CAA) is a common cerebrovascular disease characterized by beta-amyloid (Aβ) accumulation in the cerebral vasculature, resulting in vascular cognitive impairment and dementia (VCID) along with other neuropathologies such as inflammation. Given that medications approved to treat CAA currently do not exist, this highlights that there is a pressing need for more innovative approaches to drug discovery. In this study, classical renin-angiotensin system (RAS)-inhibiting antihypertensive drugs were repurposed to investigate their efficacy for mitigating CAA-associated neuropathology and cognitive decline, while additionally evaluating for sex-specific outcomes. Male and female Tg-SwDI mice were treated for 4 months with non-hypotensive doses of either telmisartan [angiotensin II receptor blocker (ARB)] or lisinopril [angiotensin-converting enzyme (ACE) inhibitor] starting at 8 months old. Blood pressure was measured 2 and 4 months into treatment, then behavioral tests were conducted to assess learning and memory. Histochemical analyses of brain sections were performed to observe Aβ pathology, neuroinflammatory markers, and vasculopathy. Behavioral testing indicated that both drugs improved some cognitive outcomes in the affected mice, and ongoing investigations aim to identify mechanisms of neuroprotection, including potential mitigation of CAA and neuroinflammation. These findings suggest that RAS-inhibiting medications have a role beyond blood pressure control and demonstrate promise as a focus for novel drug development for treating CAA and other neuropathologies.