Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy

Cerebral deposition of the amyloid 6 protein (A beta), an invariant feature of Alzheimer's disease, reflects an imbalance between the rates of A beta production and clearance. The causes of A beta elevation in the common late-onset form of Alzheimer's disease (LOAD) are largely unknown. There is evidence that the A beta-degrading protease neprilysin (NEP) is down-regulated in normal aging and LOAD. We asked whether a decrease in endogenous NEP levels can prolong the half-life of A,6 in vivo and promote development of the classic amyloid neuropathology of Alzheimer's disease. We examined the brains and plasma of young and old mice expressing relatively low levels of human amyloid precursor protein and having one or both NEP genes silenced. NEP loss of function 1) elevated whole-brain and plasma levels of human AB(40) and A beta 42, 2) prolonged the half-life of soluble A beta in brain interstitial fluid of awake animals, 3) raised the concentration of A beta dimers, 4) markedly increased hippocampal amyloid plaque burden, and 5) led to the development of amyloid angiopathy. A similar to 50% reduction in NEP levels, similar to that reported in some LOAD brains, was sufficient to increase amyloid neuropathology. These findings demonstrate an important role for proteolysis in determining the levels of A,6 and A beta-associated neuropathology in vivo and support the hypothesis that primary defects in A beta clearance can cause or contribute to LOAD pathogenesis.