Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation.
|Abstract||Amyloid-β (Aβ) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Aβ degradation in the human brain remain unclear.|
Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in cell models and knock-in mouse brains: familial Alzheimer disease-linked mutation impairs gamma-site cleavage of amyloid precursor protein C-terminal fragment beta.
|Journal Title||neuro-degenerative diseases|
|Publication Year Start||2017-01-01|
PMID- 28103595 OWN - NLM STAT- Publisher DA - 20170119 LR - 20170119 IS - 1660-2862 (Electronic) IS - 1660-2854 (Linking) VI - 17 IP - 2-3 DP - 2017 Jan 20 TI - Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-beta Degradation. PG - 103-109 LID - 10.1159/000453358 [doi] AB - BACKGROUND: Amyloid-beta (Abeta) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Abeta degradation in the human brain remain unclear. OBJECTIVE: This study aimed to quantify the levels of small C-terminal Abeta fragments generated upon Abeta degradation in human cerebrospinal fluid (CSF). METHODS: A fraction containing small peptides was isolated and purified from human CSF by high-pressure liquid chromatography. Degradation products of Abeta C termini were identified and measured by liquid chromatography-tandem mass spectrometry. The C-terminal fragments of Abeta in the conditioned medium of cultured cells transfected with the Swedish variant of betaAPP (sw betaAPP) were analyzed. These fragments in brains of PS1 I213T knock-in transgenic mice, overexpressing sw betaAPP, were also analyzed. RESULTS: The peptide fragments GGVV and GVV, produced by the cleavage of Abeta40, were identified in human CSF as well as in the brains of the transgenic mice and in the conditioned medium of the cultured cells. Relative to Abeta40 levels, GGVV and GVV levels were 7.6 +/- 0.81 and 1.5 +/- 0.18%, respectively, in human CSF. Levels of the GGVV fragment did not increase by the introduction of genes encoding neprilysin and insulin-degrading enzyme to the cultured cells. CONCLUSION: Our results indicate that a substantial amount of Abeta40 in human brains is degraded via a neprilysin- or insulin-degrading enzyme-independent pathway. CI - (c) 2017 S. Karger AG, Basel. FAU - Mizuta, Naoki AU - Mizuta N AD - Psychiatry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. FAU - Yanagida, Kanta AU - Yanagida K FAU - Kodama, Takashi AU - Kodama T FAU - Tomonaga, Takeshi AU - Tomonaga T FAU - Takami, Mako AU - Takami M FAU - Oyama, Hiroshi AU - Oyama H FAU - Kudo, Takashi AU - Kudo T FAU - Ikeda, Manabu AU - Ikeda M FAU - Takeda, Masatoshi AU - Takeda M FAU - Tagami, Shinji AU - Tagami S FAU - Okochi, Masayasu AU - Okochi M LA - eng PT - Journal Article DEP - 20170120 PL - Switzerland TA - Neurodegener Dis JT - Neuro-degenerative diseases JID - 101189034 EDAT- 2017/01/20 06:00 MHDA- 2017/01/20 06:00 CRDT- 2017/01/20 06:00 PHST- 2016/04/04 [received] PHST- 2016/11/10 [accepted] AID - 000453358 [pii] AID - 10.1159/000453358 [doi] PST - aheadofprint SO - Neurodegener Dis. 2017 Jan 20;17(2-3):103-109. doi: 10.1159/000453358.
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