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Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects

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Title: Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects
Authors: Hata, Saori Browse this author
Taniguchi, Miyako Browse this author
Piao, Yi Browse this author
Ikeuchi, Takeshi Browse this author
Fagan, Anne M. Browse this author
Holtzman, David M. Browse this author
Bateman, Randall Browse this author
Sohrabi, Hamid R. Browse this author
Martins, Ralph N. Browse this author
Gandy, Sam Browse this author
Urakami, Katsuya Browse this author
Suzuki, Toshiharu Browse this author →KAKEN DB
Keywords: Alzheimer's disease
Cerebrospinal fluid
γ-secretase
Alcadein
β-amyloid
Issue Date: 25-Apr-2012
Publisher: BioMed Central
Journal Title: Molecular Neurodegeneration
Volume: 7
Start Page: 16
Publisher DOI: 10.1186/1750-1326-7-16
Abstract: Background: Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aβ and p3-Alcα can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcα in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). Results: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcα, we determined levels of total p3-Alcα in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Aβ40 correlated with levels of total p3-Alcα in all cohorts. Conclusions: We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3-Alcα can serve as a either (1) a nonaggregatable surrogate marker for γ-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alcα and Aβ40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of γ-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Aβ metabolism.
Rights: http://creativecommons.org/licenses/by/2.0/
Type: article
URI: http://hdl.handle.net/2115/50159
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 利治

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