Student Theses, Dissertations and Capstones

Document Type

Dissertation - NSU Access Only

Degree Name

Doctor of Philosophy (PhD) in Pharmacy

First Advisor

Robert Speth

Second Advisor

Lisa Robison

Defense Date

1-1-2025

Abstract

Cerebral amyloid angiopathy (CAA) results from beta-amyloid accumulation around the cerebral vasculature. It is associated with cognitive impairment and other neurological pathologies, in many cases co-existing with Alzheimer’s disease (AD). Currently, there are no drugs available to prevent, or efficiently treat, neurodegenerative diseases such as CAA and AD, only to temporarily alleviate their symptoms. This study aimed to determine if FDA-approved drugs that target the renin-angiotensin system (RAS) that are typically prescribed to treat hypertension can be repurposed to target the brain’s RAS, since its vascular and parenchymal components are also present in the brain. Additionally, it aimed to determine whether these benefits are sex- and disease stage-specific. We hypothesized that drugs that target the RAS would mitigate CAA pathology in the Tg-SwDI mouse model of the disease. The effects of chronic oral treatment with two drugs hypothesized to be protective in the Tg-SwDI mouse were assessed: 1) Telmisartan [a brain penetrant angiotensin II type 1 receptor (AT1R) blocker (ARB)], and 2) Lisinopril [an angiotensin-converting enzyme (ACE) inhibitor]. Animals were treated with the drugs for five months, starting at three months of age, and underwent behavior testing at seven months of age, before being euthanized at eight months of age. Blood pressure was monitored two and four months after the start of drug treatment. Following euthanasia, brains were assessed for AT1R binding in different regions, as well as vasculopathy and neuropathological changes. Results showed that RAS-inhibiting drugs had some cognitive benefits that were task- and sex-specific with mixed results seen in neuropathology. In conclusion, the study reveals potential benefits of the use of RAS-inhibiting drugs to mitigate neurodegenerative changes associated with CAA.

Subject Categories

Pharmacy and Pharmaceutical Sciences

Keywords

Amyloid-beta; Cerebral amyloid angiopathy; Neurodegenerative diseases; Renin-angiotensin system; Tg-SwDI mice

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