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Open Access 01-12-2012 | Research article

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

Authors: Saori Hata, Miyako Taniguchi, Yi Piao, Takeshi Ikeuchi, Anne M Fagan, David M Holtzman, Randall Bateman, Hamid R Sohrabi, Ralph N Martins, Sam Gandy, Katsuya Urakami, Toshiharu Suzuki, the Japanese Alzheimer's Disease Neuroimaging Initiative

Published in: Molecular Neurodegeneration | Issue 1/2012

Abstract

Background

Alcadein_α (Alc_α) 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 Alc_α by α- and γ-secretases generates non-aggregatable p3 or p3-Alc_α peptides. Aβ and p3-Alc_α can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alc_α 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-Alc_α, we determined levels of total p3-Alc_α 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-Alc_α in all cohorts.

Conclusions

We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3-Alc_α 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-Alc_α 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 metabolis

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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: Saori Hata
Miyako Taniguchi
Yi Piao
Takeshi Ikeuchi
Anne M Fagan
David M Holtzman
Randall Bateman
Hamid R Sohrabi
Ralph N Martins
Sam Gandy
Katsuya Urakami
Toshiharu Suzuki
the Japanese Alzheimer's Disease Neuroimaging Initiative
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2012
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/1750-1326-7-16

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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