Metabolic regulation of brain Abeta by neprilysin.
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.
Iwata
N
N
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Tsubuki
S
S
Takaki
Y
Y
Shirotani
K
K
Lu
B
B
Gerard
N P
NP
Gerard
C
C
Hama
E
E
Lee
H J
HJ
Saido
T C
TC
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D018628:Gene Dosage; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D020218:Response Elements; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D015260:Neprilysin