Targeting the Renin-Angiotensin System for the Treatment of Cerebral Amyloid Angiopathy

Targeting the Renin-Angiotensin System for the Treatment of Cerebral Amyloid Angiopathy

Alvin Sherman Library

Cerebral amyloid angiopathy (CAA), the accumulation of amyloid proteins in the cerebral vasculature, can increase the risk of stroke, vascular cognitive impairment, and dementia. CAA is highly comorbid with Alzheimer’s disease and contributes to Alzheimer’s pathology by affecting the clearance of amyloid from the brain. Epidemiological studies suggest that certain renin-angiotensin system-targeting drugs, commonly used for the treatment of hypertension, decrease the risk of dementia. This study assesses whether two FDA-approved RAS-targeting drugs: telmisartan [a brain-penetrant angiotensin receptor blocker (ARB)], and lisinopril [a brain-penetrant angiotensin-converting enzyme (ACE) inhibitor]; can be repurposed to mitigate CAA, associated neuropathologies, and cognitive decline in a transgenic mouse model (Tg-SwDI). At ~4 or 8 months of age, male and female Tg-SwDI mice began treatment with telmisartan (1 mg/kg/day) or lisinopril (15 mg/kg/day) or received plain drinking water. Age and sex-matched C57Bl/6J mice receiving plain drinking water served as controls. Following 4 months of treatment, mice underwent blood pressure measurement, behavioral testing, and post-mortem brain analysis. Telmisartan and lisinopril treatment did not significantly reduce blood pressure in TgSwDI mice; these results are as expected since the goal was to supply subpressor doses. Data collected thus far suggests that RAS targeting drugs have the potential to mitigate some of the cognitivebehavioral impairments in Tg-SwDI mice, despite little observed improvement in AT1R, amyloid pathology, and neuroinflammation. If findings support our hypothesis, this will demonstrate that these drugs could be repurposed to prevent and/or treat individuals with CAA, reducing the worldwide burden of stroke and dementia.