Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ-Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Neprilysin (NEP), which degrades amyloid-beta (A beta), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in epsilon 2-positive and lowest in epsilon 4-positive brains. To assess the role of NEP in protecting CVSMCs from A beta toxicity, we measured cell death in primary human adult CVSMCs exposed to A beta(1-40), A beta(1-42) or A beta(1-40) (Dutch variant). A beta(1-42) was most cytotoxic to CVSMCs. A beta(1-42)-mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely A beta(1-42)-mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from A beta toxicity and protects cerebral blood vessels from the development and complications of CAA.