Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology

Alzheimer's disease is characterized by neuronal loss and cerebral accumulation of amyloid-beta protein (A beta) and lowering the generation of A beta is a pivotal approach in the strategy of Alzheimer's disease treatment. Midlife hypertension is a major risk factor for the future onset of sporadic Alzheimer's disease and the use of some antihypertensive drugs may decrease the incidence of Alzheimer's disease. However, it is largely unknown how the blood pressure regulation system is associated with the pathogenesis of Alzheimer's disease. Here we found that the deficiency of angiotensin type 1a receptor (AT1a), a key receptor for regulating blood pressure, significantly decreased A beta generation and amyloid plaque formation in a mouse model of Alzheimer's disease. The lack of AT1a inhibited the endocleavage of presenilin-1 (PS1), which is essential for gamma-secretase complex formation and A beta generation. Notably, the ligand of AT1a, angiotensin II, enhanced A beta generation, PS1 endocleavage and gamma-secretase complex formation. Our results suggest that AT1a activation is closely associated with A beta generation and brain amyloid accumulation by regulating gamma-secretase complex formation. Thus, removal of life style factors or stresses that stimulate AT1a to elevate blood pressure may decrease A beta generation and brain amyloid accumulation, thereby preventing the pathogenesis of Alzheimer's disease.