AT2R’s (Angiotensin II Type 2 Receptor’s) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease

Abstract

Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers’ cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan’s benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan’s benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan’s benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aβ (amyloid β) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aβ plaques, but not diffuse plaques or Aβ species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aβ-related cognitive and cerebrovascular deficits.

Dysfunctional vascular smooth muscle cells mediate early and late-stage neuroinflammation and Tau hyperphosphorylation

“…While the majority of AD studies have focused on neural and glial cells, this study extends the catalog of promoting factors in AD which promise to enable development of new therapeutic interventions and vascular-related biomarkers for early detection of the disease. In this context, recent studies have showed that targeting the vascular tissue with drugs such as Losartan, ACEi or Captopril could help to improve memory and cognitive decline (Lee et al, 2020;Royea et al, 2020;Royea et al, 2020;Asraf et al, 2018;Rahimi et al, 2020). Therefore, this study supports the idea of VSMCs as a novel therapeutic target in AD.…”

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…Early studies investigated cognitive effects of ARBs in animals. It was shown that pretreatment with losartan reduced chronic ethanol-induced cognitive deficits (Tracy et al, 1997) and improved both spatial and short-term working memory in animals (Raghavendra et al, 1998;Royea et al, 2020). It was shown that telmisartan has a long term anti-inflammatory effect by modulating microglia in vitro and in vivo (Torika et al, 2016).…”

Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease

“…While most AD studies have focused on neural and glial cells, this study extends the catalog of promoting factors in AD which promise to enable development of new therapeutic interventions and vascular-related biomarkers for early detection of the disease. In this context, recent studies have showed that targeting the vascular tissue with drugs such as Losartan, ACEi, or Captopril could help to improve memory and cognitive decline ( Lee et al., 2020 ; Royea et al., 2020 ; Royea et al., 2020 , 2020 ; Asraf et al., 2018 ; Rahimi et al, 2021 ). Therefore, this study supports the idea of VSMCs as promising therapeutic targets in AD.…”