Metabolic regulation of brain Abeta by neprilysin

Science. 2001 May 25;292(5521):1550-2. doi: 10.1126/science.1059946.

Abstract

Amyloid beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate Abeta-degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered Abeta and in the metabolic suppression of the endogenous Abeta levels in a gene dose-dependent manner. The regional levels of Abeta 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 Abeta 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 Abeta accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / enzymology
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid
  • Down-Regulation
  • Enhancer Elements, Genetic
  • Enzyme-Linked Immunosorbent Assay
  • Gene Dosage
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • Neprilysin / genetics
  • Neprilysin / metabolism*
  • Neurons / enzymology
  • Peptide Fragments / metabolism
  • Presenilin-1
  • Response Elements
  • Up-Regulation

Substances

  • Amyloid beta-Peptides
  • Membrane Proteins
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • Neprilysin