Alzheimer’s Disease Augments Cerebrovascular Apoptosis to Oxidative Stress in Males and Females at Different Stages of Diseases Progression

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by vascular rarefaction and cognitive decline. Oxidative stress and mitochondrial dysfunction are crucial in AD progression, however how AD alters vascular cell survival during acute oxidative stress remains undefined. While healthy aging enhances vascular resilience to oxidative stress, we hypothesized that AD increases apoptosis of smooth muscle (SMC) and endothelial cells (EC) to acute oxidative stress by increasing mitochondrial ROS production and depolarization of mitochondrial membrane potential (ΔΨ m ). Posterior cerebral arteries (PCA; ~80 µm diameter) from male and female 3xTG AD mice—examined at various stages of disease progression, including young (YH - 2-3 months), cognitively impaired (CI - 4-5 months) and amyloid beta plaques (Aβ - 6-8 months)—were isolated, cannulated, and pressurized to 90 cm H 2 O at 36°C. The effect of AD on resting mitochondrial ROS production in PCAs was evaluated with MitoSox (5 µM). ROS production was modestly augmented (p<0.05) in vessels from CI mice and further augmented in Aβ mice of both sexes. SMC and EC death were quantified using Hoechst 33342 (1 µM - stains all nuclei) and propidium iodide (1 µM - staining dead nuclei) after 50 min exposure to H 2 O 2 (200 µM). SMC and EC death were <10% in young healthy control PCAs from males and females. Apoptosis was enhanced in both cell types in vessels from male Aβ mice (~ 20%) compared to YH and CI (<=10%). While SMCs from female CI mice exhibit significantly (p<0.05) higher death (~ 20%) compared to YH, SMCs from Aβ mice did not have greater susceptibility to H 2 O 2 (<10% cell death). EC death in females showed similar trends. Given that depolarization of ΔΨ m is a critical event for the initiation of intrinsic apoptosis, we assessed changes in ΔΨ m during exposure to H 2 O 2 with tetramethylrhodamine methyl ester (TMRM, 10 nM). For males, exposure to H 2 O 2 exasperated depolarization of ΔΨ m in pressurized PCAs from Aβ compared to CI or YH mice. In females, H 2 O 2 evoked the greatest ΔΨ m depolarization in PCAs from CI mice consistent with the high cell death in these vessels. We conclude that AD increases ROS production in cerebral arteries and enhances sensitivity to ROS-mediated cell death. Furthermore, apoptosis is elevated in different phases of AD in males and females providing insight into the progression of vessel rarefaction linked to cognitive decline. AARG-NTF-23-1148948 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.