Hypertension enhances Aβ-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP

Abstract

Hypertension (HTN) doubles the risk of Alzheimer’s disease (AD), but the mechanisms remain unclear. Amyloid- β (A β), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with A β to amplify its deleterious cerebrovascular effects and to increase A β production. Infusion of angiotensin II (ANGII; intravenously) elevated blood pressure and attenuated the cerebral blood flow (CBF) response to whisker stimulation or the endothelium-dependent vasodilator acetylcholine (ACh) ( P < 0.05). Neocortical application of A β in mice receiving ANGII worsened the responses to ACh ( P < 0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which A β is elevated both in blood and in brain due to expression of mutated amyloid precursor protein (APP), was not aggravated by neocortical application of ANGII or by a 2-week administration of ‘slow pressor’ of ANGII (600 ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which A β is increased only in brain. Slow-pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced β-secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing A β, ANGII increased β-secretase activity, A β1–42, and the A β42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD.