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

Filip Liebsch, Luka Kulic, Charlotte Teunissen, Adeola Shobo, Irem Ulku, Vivienne Engelschalt, Mark A. Hancock, Wiesje M. Flier, Peter Kunach, Pedro Rosa-Neto, Philip Scheltens, Judes Poirier, Paul Saftig, Randall J. Bateman, John Breitner, Christoph Hock and Gerhard Multhaup ()
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Filip Liebsch: McGill University
Luka Kulic: University of Zurich
Charlotte Teunissen: Amsterdam UMC, Vrije Universiteit Amsterdam
Adeola Shobo: McGill University
Irem Ulku: McGill University
Vivienne Engelschalt: Freie Universität Berlin
Mark A. Hancock: McGill University
Wiesje M. Flier: Vrije Universiteit Amsterdam
Peter Kunach: Douglas Research Institute, McGill University
Pedro Rosa-Neto: Douglas Research Institute, McGill University
Philip Scheltens: Vrije Universiteit Amsterdam
Judes Poirier: McGill University
Paul Saftig: Christian-Albrechts-Universität-Kiel
Randall J. Bateman: Washington University in St. Louis
John Breitner: McGill University
Christoph Hock: University of Zurich
Gerhard Multhaup: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10152-w

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