Targeting the Renin Angiotensin System Ameliorates Cognitive Dysfunction in Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenemia and insulin resistance. PCOS women experience memory and executive function impairments that are correlated with plasma androgens and insulin levels. The molecular mechanisms underlying cognitive impairment in PCOS is unknown. Tau hyperphosphorylation is a recognized hallmark of Alzheimer’s disease (AD) and other cognitive disorders. Renin Angiotensin System (RAS) dysregulation can cause cognitive impairment by increasing phosphorylated tau (p-tau) expression. Androgens differentially regulate the RAS system in both sexes. However, it’s unknown if androgens excess induces central RAS dysregulation, contributing to cognitive impairment in PCOS. We aim to test the hypothesis that ‘’In females, hyperandrogenemia induces RAS dysregulation and tau hyperphosphorylation in brain areas involved in cognition and memory, resulting in cognitive impairment that can be mitigated with RAS-targeted therapies. Methods: PCOS was induced in three-week-old female mice using Silastic tubes implantation of the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg, sc, 90 days) or vehicle (n = 6/grp). Eight weeks later, the mice were given the centrally acting angiotensin II type 1 receptor (AT1R) blocker telmisartan (5 mg/kg/day) or the angiotensin converting enzyme (ACE) inhibitor perindopril (1mg/kg/day) for 4 weeks. Weekly body weight (BW, gravimetry) and composition (EchoMRI) were assessed. Glucose homeostasis was measured by oral glucose tolerance test (OGTT). Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin. The expression of androgen receptor (AR), RAS components (renin, angiotensinogen, angiotensin II type 2 receptor [AT2R], ACE1, ACE2, and renin receptor), p-tau [Thr181, Thr205, and S404], and apoptosis markers (Bax, Bcl-XL) were assessed by Western blotting in the parietal cortex, a major brain area that is involved in cognition and memory control. Spatial memory and learning were assessed using the Barnes Maze behavioral assay, while the exploratory tendencies were measured using in Open Field test (20 min). Results: DHT significantly (p < 0.05) increased BW (25.1 ± 0.5 vs 21.8 ± 0.5 g, and fat mass (4.6 ± 0.5 vs 2.0 ± 0.1 g), impaired OGTT (186.1 ± 6.0 vs 250.7 ± 14.8 mg.min/dL), and increased HOMA-IR (1.8-fold). In the parietal cortex, PCOS mice have higher AR, renin, angiotensinogen, and AT2R levels, but no significant changes were seen in ACE2 and renin receptor expression. These changes were associated with increased p-tau (S404 and Th181) and apoptosis (higher Bax levels). The results from the Barnes maze assay showed that PCOS mice have higher latency to reach the target hole (31.03 ±9.94 vs. 18.85±4.86 s), indicating spatial learning and memory impairment. Additionally, PCOS mice show decreased exploratory tendencies (longer time spent in center) in the open field test. Treatment with telmisartan or perindopril effectively reversed these DHT-induced behavioral impairments. Conclusion and significance: Our findings suggest that hyperandrogenemia drives RAS dysregulation, contributing to cognitive deficits that can be improved with RAS-targeted therapies. The study highlights RAS-acting drugs as novel therapeutic approaches to prevent or mitigate the onset and progression of cognitive dysfunction in PCOS. Supported by NIH grants NIGMS P20GM121334 (SR, KSE, and DGR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.