Localization of mature neprilysin in lipid rafts

Kimihiko Sato, Chiaki Tanabe, Yoji Yonemura, Haruhiko Watahiki, Yimeng Zhao, Sosuke Yagishita, Maiko Ebina, Satoshi Suo, Eugene Futai, Masayuki Murata, Shoichi Ishiura

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Alzheimer's disease (AD) is characterized by senile plaques caused by amyloid-β peptide (Aβ) accumulation. It has been reported that Aβ generation and accumulation occur in membrane microdomains, called lipid rafts, which are enriched in cholesterol and glycosphingolipids. Moreover, the ablation of cholesterol metabolism has been implicated in AD. Neprilysin (NEP), a neutral endopeptidase, is one of the major Aβ-degrading enzymes in the brain. Activation of NEP is a possible therapeutic target. However, it remains unknown whether the activity of NEP is regulated by its association with lipid rafts. Here we show that only the mature form of NEP, which has been glycosylated in the Golgi, exists in lipid rafts, where it is directly associated with phosphatidylserine. Moreover, the localization of NEP in lipid rafts is enhanced by its dimerization, as shown using the NEP E403C homodimerization mutant. However, the protease activities of the mature form of NEP, as assessed by in vitro peptide hydrolysis, did not differ between lipid rafts and nonlipid rafts. We conclude that cholesterol and other lipids regulate the localization of mature NEP to lipid rafts, where the substrate Aβ accumulates but does not modulate the protease activity of NEP.

Original languageEnglish
Pages (from-to)870-877
Number of pages8
JournalJournal of Neuroscience Research
Issue number4
Publication statusPublished - 2012 Apr


  • Alzheimer's disease
  • Lipid rafts
  • Neprilysin


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