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Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer's Disease

The use of angiotensin receptor blockers (ARBs) correlates with reduced onset and progression of Alzheimer's disease (AD). The mechanism depicting how ARBs such as losartan restore cerebrovascular and cognitive deficits in AD is unknown. Here, we propose a mechanism underlying losartan's benefits by selectively blocking the effects of angiotensin IV (AngIV) at its receptor (AT4R) with divalinal in mice overexpressing the AD-related Swedish and Indiana mutations of the human amyloid precursor protein (APP mice) and WT mice. Young (3-month-old) mice were treated with losartan (∼10 mg/kg/d, 4 months), followed by intracerebroventricular administration of vehicle or divalinal in the final month of treatment. Spatial learning and memory were assessed using Morris water mazes at 3 and 4 months of losartan treatment. Cerebrovascular reactivity and whisker-evoked neurovascular coupling responses were measured at end point (∼7 months of age), together with biomarkers related to neuronal and vascular oxidative stress (superoxide dismutase-2), neuroinflammation (astroglial and microglial activation), neurogenesis (BrdU-labeled newborn cells), and amyloidosis [soluble amyloid-β (Aβ) species and Aβ plaque load]. Divalinal countered losartan's capacity to rescue spatial learning and memory and blocked losartan's benefits on dilatory function and baseline nitric oxide bioavailability. Divalinal reverted losartan's anti-inflammatory effects, but failed to modify losartan-mediated reductions in oxidative stress. Neither losartan nor divalinal affected arterial blood pressure or significantly altered the amyloid pathology in APP mice. Our findings identify activation of the AngIV/AT4R cascade as the underlying mechanism in losartan's benefits and a target that could restore Aβ-related cognitive and cerebrovascular deficits in AD. SIGNIFICANCE STATEMENT Antihypertensive medications that target the renin angiotensin system, such as angiotensin receptor blockers (ARBs), have been associated with lower incidence and progression of Alzheimer's disease (AD) in cohort studies. However, the manner by which ARBs mediate their beneficial effects is unknown. Here, the angiotensin IV receptor (AT4R) was identified as mediating the cognitive and cerebrovascular rescue of losartan, a commonly prescribed ARB, in a mouse model of AD. The AT4R was further implicated in mediating anti-inflammatory benefits. AT4R-mediated effects were independent from changes in blood pressure, amyloidosis, and oxidative stress. Overall, our results implicate the angiotensin IV/AT4R cascade as a promising candidate for AD intervention.