title: Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease.
abstract: Amyloid beta peptide (A beta) 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 A beta-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 A beta-induced synaptic toxicity, and the support the potential benefits of neprilysin up-regulation in ameliorating neuropathology in prodromal and early AD.
authors.affiliation: Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maruyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Takaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Matsuba
authors.forename: Haruko
authors.initials: H
authors.lastname: Tanji
authors.forename: Miyako
authors.initials: M
authors.lastname: Nemoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tomita
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsui
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Hidetada
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid* / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D015536:Down-Regulation; D042241:Early Diagnosis; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D015260:Neprilysin / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics; D051381:Rats
chemical_list: D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; D015260:Neprilysin; D007608:Kainic Acid