Role of Angiotensin II on Cardiovascular/Autonomic Function and Cognition in a Novel Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Despite being the most common form of dementia in the elderly, mechanisms causing AD remain elusive. Emerging evidence have associated brain renin-angiotensin system (RAS) to AD neuropathology. RAS actions are predominantly mediated by angiotensin II (Ang II) binding to type 1 receptors. Previously, we have observed that human apolipoprotein E4-knockin (risk factor for AD) mice develop progressive hypertension and increases in Ang II levels in CSF with aging [FASEB J 36(S1): R3532]. Thus, we hypothesize that Ang II-mediated hypertension contributes to cognitive decline in AD. We have generated a novel transgenic mouse model of AD i.e. 3XE4 by breeding E4-knockin mouse with APPsw, PS1dE9, and tauP301S transgenes, to mimic human AD pathology in mice. Blood pressure (BP) and heart rate (HR) were measured by radiotelemetry in 3XE4 (n=6) and control 3XE3 (n=6) mice, before and after 28-days of Ang II infusion (1000 ng/kg/min, osmotic pump). Diurnal BP variability was calculated as the difference between night-time (11:00 PM-3:00 AM) and day-time (8:00 AM-12:00 PM). Cardiac vagal and sympathetic tones were calculated as changes in HR with atropine and propranolol (1 mg/kg each, IP), respectively. Cardiac function (echocardiography) and cognitive behavior (novel object recognition test) were measured. At baseline, BP was similar in control (127±11 mmHg) and 3XE4 (123±5 mmHg) mice. Unlike the control mice, 3XE4 mice exhibit reduced vagal tone (ΔHR= +119±22 vs. +25±24 bpm) and increased sympathetic tone (ΔHR= -76±33 vs. -212±40 bpm), which worsens with Ang II (p<0.05 vs. baseline). Interestingly, Ang II increased BP (24%), induced LV hypertrophy (26%), impaired diurnal BP variability, and evoked learning and memory deficits; albeit only in the 3XE4 mice (p<0.05 vs. control mice). These results demonstrate that Ang II-mediated hypertension and autonomic dysfunction likely exacerbate disease progression and cognitive decline in the 3XE4 mouse model of AD. Therefore, our study provides a proof-of- concept in delineating the association of ApoE4 genotype and Ang II with Alzheimer’s disease. NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.