Repurposing Renin-Angiotensin System-Targeting Medications for Later Stage Treatment of Cerebral Amyloid Angiopathy and Associated Cognitive-Behavioral Deficits in Tg-SwDI mice
Abstract
Cerebral amyloid angiopathy (CAA), the accumulation of amyloid proteins in the cerebral vasculature, is highly comorbid with Alzheimer’s disease, and on its own, increases the risk of stroke and vascular dementia. Epidemiological studies suggest that certain renin-angiotensin system (RAS)-targeting drugs, commonly used for treating hypertension, decrease the risk of dementia. This study assesses whether two FDA-approved RAS-targeting drugs: telmisartan [a moderately brain-penetrant angiotensin receptor blocker (ARB)], and lisinopril [a brain-penetrant angiotensin-converting enzyme (ACE) inhibitor]; can be repurposed to treat CAA. At ~8 months of age, male and female Tg-SwDI mice (CAA model) began treatment with telmisartan (1 mg/kg/day) or lisinopril (15 mg/kg/day) or received plain water only. C57BL/6J mice receiving plain water served as wild-type controls. At ~12 months, mice underwent blood pressure measurement, behavioral testing, and post-mortem brain analysis. Voluntary oral consumption delivered doses similar to the target dose for both drugs. Telmisartan and lisinopril treatment did not significantly reduce blood pressure in Tg-SwDI mice; these results are as expected since the goal was to supply subpressor doses. While neither drug treatment normalized the decreased activity levels displayed by Tg-SwDI mice in the open field, lisinopril decreased anxiety-like behavior. Preliminary findings suggest that drug treatment, particularly lisinopril, may mitigate cognitive deficits observed in Tg-SwDI mice in the Barnes maze. Ongoing experiments are being completed to increase sample sizes and investigate the potential benefits of telmisartan and lisinopril on neuropathology in TgSwDI mice. If findings support our hypothesis, this will demonstrate that these drugs could be repurposed to treat CAA.
Faculty Sponsors
Dr. Robert Speth, Dr. Lisa Robinson
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-3-2024 12:30 PM
End Date
4-4-2024 1:30 PM
Repurposing Renin-Angiotensin System-Targeting Medications for Later Stage Treatment of Cerebral Amyloid Angiopathy and Associated Cognitive-Behavioral Deficits in Tg-SwDI mice
Alvin Sherman Library
Cerebral amyloid angiopathy (CAA), the accumulation of amyloid proteins in the cerebral vasculature, is highly comorbid with Alzheimer’s disease, and on its own, increases the risk of stroke and vascular dementia. Epidemiological studies suggest that certain renin-angiotensin system (RAS)-targeting drugs, commonly used for treating hypertension, decrease the risk of dementia. This study assesses whether two FDA-approved RAS-targeting drugs: telmisartan [a moderately brain-penetrant angiotensin receptor blocker (ARB)], and lisinopril [a brain-penetrant angiotensin-converting enzyme (ACE) inhibitor]; can be repurposed to treat CAA. At ~8 months of age, male and female Tg-SwDI mice (CAA model) began treatment with telmisartan (1 mg/kg/day) or lisinopril (15 mg/kg/day) or received plain water only. C57BL/6J mice receiving plain water served as wild-type controls. At ~12 months, mice underwent blood pressure measurement, behavioral testing, and post-mortem brain analysis. Voluntary oral consumption delivered doses similar to the target dose for both drugs. Telmisartan and lisinopril treatment did not significantly reduce blood pressure in Tg-SwDI mice; these results are as expected since the goal was to supply subpressor doses. While neither drug treatment normalized the decreased activity levels displayed by Tg-SwDI mice in the open field, lisinopril decreased anxiety-like behavior. Preliminary findings suggest that drug treatment, particularly lisinopril, may mitigate cognitive deficits observed in Tg-SwDI mice in the Barnes maze. Ongoing experiments are being completed to increase sample sizes and investigate the potential benefits of telmisartan and lisinopril on neuropathology in TgSwDI mice. If findings support our hypothesis, this will demonstrate that these drugs could be repurposed to treat CAA.
