Sexual dimorphism in AngII/AT1R‐mediated cognitive and cardiovascular dysfunction in a mouse model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population (>65 years). AD is pathologically characterized by the presence of amyloid‐beta plaques (Aβ) and neurofibrillary tangles (Tau) in the brain. Progressive increases in systolic blood pressure (SBP) and BP variability (BPV) with aging, likely contribute to cognitive decline. Moreover, blockade of angiotensin II (AngII) actions on type 1 receptors (AT1R) has been shown to be effective against dementia and autonomic dysfunction. Therefore, we hypothesized that enhanced AngⅡ/AT1R signaling contributes to cognitive and cardiovascular/autonomic decline in AD. Apolipoprotein E4 (ApoE4) is the most prevalent genetic risk factor associated with AD. In this study, we have utilized human ApoE4‐knockin (E4) and human ApoE3‐knockin (E3) mice. SBP and heart rate (HR) were measured by telemetry in E3 (n=7) and E4 (n=11) mice beginning from 10 weeks to 70 weeks of age. BPV was calculated as SD of BP, while resting cardiac sympathetic tone was estimated as the HR response to b‐adrenergic receptor antagonist propranolol (2 mg/kg, IP). Quantitative polymerase chain reaction (qPCR) was used to measure expression of AT1R in the hippocampus (HC; brain site for learning and memory), paraventricular nucleus of hypothalamus (PVN; brain site for cardiovascular/autonomic regulation), left ventricle (LV; heart) and skeletal muscle (SKM; quadriceps). At 10 weeks of age, there were no significant differences in SBP, BPV, sympathetic tone and cognition (Barnes maze) between E3 and E4 mice. Notably, female E4 mice exhibited increases in SBP, increases in BPV, exaggerated sympathetic tone, and cognitive decline >40 weeks of age (p<0.05 vs. E4 males). Moreover, AngⅡ in cerebrospinal fluid (CSF) was markedly increased in female E4 mice (p<0.05 vs.E4 males). In contrast, E3 mice did not exhibit significant sex differences with aging. At 10 weeks of age, AT1R expression in HC, PVN and LV was greater in the female E4 mice, and continued to increase further with aging (p<0.01‐0.0001 vs.male E4 and E3 mice). Surprisingly, AT1R expression in the LV of E4 female mice was 10‐times higher versus other tissues, despite normal cardiac function (mouse echocardiography). Collectively, the data from this study suggests that enhanced AngⅡ/AT1R signaling in the female ApoE4 carriers, contributes to cardiovascular and cognitive decline with aging.