Central Renin Angiotensin System Dysregulation in the Parietal Cortex of Hyperandrogenic Female Mice: Implications for Cognitive Dysfunction in PCOS Women

Abstract ID 96943 Poster Board 327 Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism 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 inducing mitochondrial dysfunction and increased phosphorylated tau (p-tau) expression. Androgens differentially regulate the RAS system in both sexes and negatively impact mitochondrial function in peripheral tissues in PCOS. It's unknown if excess androgens induce central RAS dysregulation or mitochondrial dysfunction, contributing to cognitive impairment in PCOS. We aim to test the hypothesis that ''In females, hyperandrogenemia induces RAS dysregulation, mitochondrial dysfunction, and tau hyperphosphorylation in brain areas involved in cognition and memory control, posing a risk for cognitive impairment in PCOS''. Methods: PCOS was induced in three-week-old female mice using Silastic tubes implantation of the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg, sc) or vehicle (n = 6/grp) for 90 days. 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], angiotensin converting enzyme1 [ACE1], ACE2, and renin receptor), mitochondrial markers (pyruvate dehydrogenase, mitochondrial stress protein HSP60, and voltage-dependent anion channel [VDAC]), p-tau [Thr181, Thr205, and S404], and apoptosis markers (Bax, Bcl-XL) was assessed by Western blotting in the parietal cortex, a major brain area that is involved in cognition and memory control. Mitochondrial reactive oxygen species (mtROS, Amplex Red assay) and mitochondrial complexes I and II-driven respiration along with complex IV activity (Oroboros fluorespirometer) were assessed in freshly isolated parietal cortex mitochondria. 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 in ACE2 and renin receptor expression. PCOS mice showed increased VDAC expression (2.6-fold), higher mtROS levels (3.05 ± 0.49 vs. 1.41 ± 0.21 % electron leak), and lower complex IV activity (30%). These changes were associated with increased p-tau (S404 and Th181) and apoptosis (higher Bax levels). Conclusion and Significance: Our findings suggest that hyperandrogenemia causes RAS dysregulation that may play a role in PCOS-associated cognitive and memory deficits by inducing mitochondrial dysfunction and/or tau phosphorylation. The study highlights mitochondrial specific targeted therapies or RAS-acting drugs as novel therapeutic approaches to prevent or mitigate the onset and progression of cognitive dysfunction in PCOS.