Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

Authors:
Filip Liebsch
Filip Liebsch
McGill University
Canada
Luka Kulic
Luka Kulic
University of Zurich
Switzerland
Charlotte Teunissen
Charlotte Teunissen
Neurochemistry Laboratory and Biobank
Dr Adeola Shobo, PhD
Dr Adeola Shobo, PhD
McGill University
Dr
Montreal , McGill University | Canada
Vivienne Engelschalt
Vivienne Engelschalt
Freie Universität Berlin
Berlin | Germany
Mark A Hancock
Mark A Hancock
McGill University
Montréal | Canada

Nat Commun 2019 05 20;10(1):2240. Epub 2019 May 20.

Department of Pharmacology and Therapeutics and Integrated Program in Neuroscience, McGill University, Montreal, QC, H3G 1Y6, Canada.

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.

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http://dx.doi.org/10.1038/s41467-019-10152-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527709PMC
May 2019
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