[Amyloid-beta peptide metabolism and Alzheimer's disease].
The deposition of amyloid-beta peptide (Abeta) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Abeta degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Abeta levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Abeta deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Abeta are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Abeta levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Abeta levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Abetalevels pharmacologically by the manipulation of neprilysin activity.
Iwata
Nobuhisa
N
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. iwatan@brain.riken.go.jp
Saido
Takaomi C
TC
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D015260:Neprilysin / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000627:therapeutic use; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D009479:Neuropeptides; D018013:Receptors, Neuropeptide; D015260:Neprilysin