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

Hypertension (HTN) doubles the risk of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid- (A), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with A to amplify its deleterious cerebrovascular effects and to increase A 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 in mice receiving ANGII worsened the responses to ACh (P<0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which A 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 (600ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which A is increased only in brain. Slow-pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced -secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing A, ANGII increased -secretase activity, A1-42, and the A42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD.