Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease

Masahiro Maruyama, Makoto Higuchi, Yoshie Takaki, Yukio Matsuba, Haruko Tanji, Miyako Nemoto, Naoki Tomita, Toshifumi Matsui, Nobuhisa Iwata, Hiroaki Mizukami, Shin Ichi Muramatsu, Keiya Ozawa, Takaomi C. Saido, Hiroyuki Arai, Hidetada Sasaki

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


Amyloid β peptide (Aβ) has been implicated in Alzheimer's disease (AD) as an initiator of the pathological cascades. Several lines of compelling evidence have supported major roles of Aβ-degrading enzyme neprilysin in the pathogenesis of sporadic AD. Here, we have shown a substantial reduction of cerebrospinal fluid (CSF) neprilysin activity (CSF-NEP) in patients with AD-converted mild cognitive impairment and early AD as compared with age-matched control subjects. The altered CSF-NEP likely reflects changes in neuronal neprilysin, since transfer of neprilysin from brain tissue into CSF was demonstrated by injecting neprilysin-carrying viral vector into the brains of neprilysin-deficient mice. Interestingly, CSF-NEP showed an elevation with the progression of AD. Along with a close association of CSF-NEP with CSF tau proteins, this finding suggests that presynaptically located neprilysin can be released into CSF as a consequence of synaptic disruption. The impact of neuronal damages on CSF-NEP was further demonstrated by a prominent increase of CSF-NEP in rats exhibiting kainate-induced neurodegeneration. Our results unequivocally indicate significance of CSF-NEP as a biochemical indicator to pursue a pathological process that involves decreased neprilysin activity and Aβ-induced synaptic toxicity, and the support the potential benefits of neprilysin up-regulation in ameliorating neuropathology in prodromal and early AD.

Original languageEnglish
Pages (from-to)832-842
Number of pages11
JournalAnnals of Neurology
Issue number6
Publication statusPublished - 2005 Jun 1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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