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C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease.

García-Ayllón, María-Salud, Lopez-Font, Inmaculada, Boix, Claudia P., Fortea, Juan, Sánchez-Valle, Raquel, Lleó, Alberto, Molinuevo, José-Luis, Zetterberg, Henrik, Blennow, Kaj, Sáez-Valero, Javier·2017·Scientific Reports
DOI 10.1038/s41598-017-02841-7PMC PMC5449401
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Abstract

This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer’s disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by η-secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD.

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Figure 1 Soluble CTFs of APP are present in human CSF. (A) Schematic representation of full-length APP processing by secretases. The epitopes for the antibodies used in this study are indicated. (B) Western blotting of three human CSF samples from non-demented controls subjects, resolved with the indicated antibody (samples were the same between different blots). (C) CSF aliquots (Total, T) were immunoprecipitated with the indicated antibody, and precipitated proteins (bound fraction, IP) were immunoblotted with the indicated alternative antibody. CSF aliquots incubated with protein A-Sepharose in the absence of capture-antibody (IPø) or with an irrelevant IgG (IPIg; a rabbit IgG for A8717 IP and a rat IgG for 2D8 IP), were analyzed in parallel as negative controls.
Figure 1 Soluble CTFs of APP are present in human CSF. (A) Schematic representation of full-length APP processing by secretases. The epitopes for the antibodies used in this study are indicated. (B) Western blotting of three human CSF samples from non-demented controls subjects, resolved with the indicated antibody (samples were the same between different blots). (C) CSF aliquots (Total, T) were immunoprecipitated with the indicated antibody, and precipitated proteins (bound fraction, IP) were immunoblotted with the indicated alternative antibody. CSF aliquots incubated with protein A-Sepharose in the absence of capture-antibody (IPø) or with an irrelevant IgG (IPIg; a rabbit IgG for A8717 IP and a rat IgG for 2D8 IP), were analyzed in parallel as negative controls.CC BY · PubMed Central
Figure 2 Higher levels of the 25-kDa APP-CTF band in the CSF of AD subjects. (A) Representative blot of the 25-kDa APP-CTF in the CSF samples from 7 symptomatic ADAD and 7 age-matched NC, which were from the same families that ADAD subjects but that did not carry mutations (black symbol; see also Table 1). Densitometric quantification of the immunoreactivity from the 25-kDa band is also shown. (B) Representative blot and densitometric quantification in CSF from 7 DS subjects with dementia of the Alzheimer’s type (dDS) and 7 age-matched NC. (C) Representative blot and densitometric quantification of the immunoreactivity from the 25-KDa APP-CTF in CSF samples from 20 sAD and 20 age-matched NC subjects. Immunodetections for (A, B, C) were performed with the A8717 antibody. p values are displayed.
Figure 2 Higher levels of the 25-kDa APP-CTF band in the CSF of AD subjects. (A) Representative blot of the 25-kDa APP-CTF in the CSF samples from 7 symptomatic ADAD and 7 age-matched NC, which were from the same families that ADAD subjects but that did not carry mutations (black symbol; see also Table 1). Densitometric quantification of the immunoreactivity from the 25-kDa band is also shown. (B) Representative blot and densitometric quantification in CSF from 7 DS subjects with dementia of the Alzheimer’s type (dDS) and 7 age-matched NC. (C) Representative blot and densitometric quantification of the immunoreactivity from the 25-KDa APP-CTF in CSF samples from 20 sAD and 20 age-matched NC subjects. Immunodetections for (A, B, C) were performed with the A8717 antibody. p values are displayed.CC BY · PubMed Central

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Cites

Research works printed but not linked: 29

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Metadata

Authors
García-Ayllón, M.-S., Lopez-Font, I., Boix, C. P., Fortea, J., Sánchez-Valle, R., Lleó, A., Molinuevo, J.-L., Zetterberg, H., Blennow, K., & Sáez-Valero, J.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-05-30
Volume
7
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-017-02841-7
PMC
PMC5449401
Cited by
51
References
3
Language
en
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