Year-end Sale % OFF 
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.
Highlights
Accumulation of the β-amyloid peptide (Aβ) in the brain is an early and specific phenomenon associated with the pathogenesis of Alzheimer’s disease (AD)[1]
In this study we investigated if amyloid precursor protein (APP)-C-terminal fragments (CTF) are detectable in cerebrospinal fluid (CSF), characterized the major APP-CTF immunoreactive band, and determined whether the levels of this peptide fragment are altered in autosomal dominant AD (ADAD), Down syndrome subjects with Alzheimer’s type dementia, and sporadic AD subjects
To determine the presence of APP-CTFs in human CSF, we first examined human CSF samples by Western blotting using three different anti-CTF antibodies. This three APP-CTF antibodies demonstrated specificity in assess the accumulation of C-terminal fragments of APP in cells transfected with a construct that encodes the C-terminal 99 amino acids of APP
Summary
Accumulation of the β-amyloid peptide (Aβ) in the brain is an early and specific phenomenon associated with the pathogenesis of Alzheimer’s disease (AD)[1]. Other plausible biomarkers for AD are additional fragments resulting from the processing of the amyloid precursor protein (APP). APP is usually cleaved by α-secretase (ADAM10; leading to non-amyloidogenic pathway), or by β-secretase (BACE1; leading to amyloidogenic pathway), which causes the secretion of large sAPPα and sAPPβ N-terminal fragments (NTFs). The membrane remaining C-terminal fragments (CTFs) are always processed by γ-secretase generating shortest intracellular domain (AICD) peptides (for a review see Haass et al.[4]). The presence in CSF of short NTF derivatives of APP, which generation does not involve α-secretase or BACE, has been demonstrated[7]. Physiological APP processing pathway driven by an asparagine endopeptidase (AEP) named δ-secretase[8] or by a metalloproteinase named η-secretase[9] will generate alternative proteolytic metabolites, including NTFs and CTFs, of different molecular mass
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
