Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease.
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.
Maruyama
Masahiro
M
Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
Higuchi
Makoto
M
Takaki
Yoshie
Y
Matsuba
Yukio
Y
Tanji
Haruko
H
Nemoto
Miyako
M
Tomita
Naoki
N
Matsui
Toshifumi
T
Iwata
Nobuhisa
N
Mizukami
Hiroaki
H
Muramatsu
Shin-ichi
S
Ozawa
Keiya
K
Saido
Takaomi C
TC
Arai
Hiroyuki
H
Sasaki
Hidetada
H
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
D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; D015260:Neprilysin; D007608:Kainic Acid