Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain.
A local increase in amyloid-beta peptide (Abeta) is closely associated with synaptic dysfunction in the brain in Alzheimer's disease. Here, we report on the catabolic mechanism of Abeta at the presynaptic sites. Neprilysin, an Abeta-degrading enzyme, expressed by recombinant adeno-associated viral vector-mediated gene transfer, was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in Abeta levels in the hippocampal formations of neprilysin-deficient mice and also reduced the increase in young mutant amyloid precursor protein transgenic mice. In the latter case, Abeta levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side, and in both sides soluble Abeta was degraded more efficiently than insoluble Abeta. Furthermore, amyloid deposition in aged mutant amyloid precursor protein transgenic mice was remarkably decelerated. Thus, presynaptic neprilysin has been demonstrated to degrade Abeta efficiently and to retard development of amyloid pathology.
Iwata
Nobuhisa
N
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan. iwatan@brain.riken.jp
Mizukami
Hiroaki
H
Shirotani
Keiro
K
Takaki
Yoshie
Y
Muramatsu
Shin-ichi
S
Lu
Bao
B
Gerard
Norma P
NP
Gerard
Craig
C
Ozawa
Keiya
K
Saido
Takaomi C
TC
D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics; D009475:Neurons, Afferent / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015260:Neprilysin