Metabolic regulation of brain Aβ by neprilysin

Amyloid beta peptide (A beta) the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate A beta -degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered A beta and in the metabolic suppression of the endogenous A beta Levels in a gene dose-dependent manner. The regional Levels of A beta in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest Level and cerebellum the lowest, correlating with the vulnerability to A beta deposition in brains of humans with AD. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting A beta accumulation.