title: Metabolism of amyloid-beta peptide and Alzheimer's disease.
abstract: The accumulation of amyloid-beta peptide (Abeta), a physiological peptide, in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD) and appears to be caused by an increase in the anabolic activity, as seen in familial AD cases or by a decrease in catabolic activity. Neprilysin is a rate-limiting peptidase involved in the physiological degradation of Abeta in the brain. As demonstrated by reverse genetics studies, disruption of the neprilysin gene causes elevation of endogenous Abeta levels in mouse brain in a gene-dose-dependent manner. Thus, the reduction of neprilysin activity will contribute to Abeta accumulation and consequently to AD development. Evidence that neprilysin in the hippocampus and cerebral cortex is down-regulated with aging and from an early stage of AD development supports a close association of neprilysin with the etiology and pathogenesis of AD. Therefore, the up-regulation of neprilysin represents a promising strategy for therapy and prevention. Recently, somatostatin, which acts via a G-protein-coupled receptor (GPCR), has been identified as a modulator that increases brain neprilysin activity, resulting in a decrease of Abeta levels. Thus, it may be possible to pharmacologically control brain Abeta levels with somatostatin receptor agonists.
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan. iwatan@brain.riken.jp
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015260:Neprilysin