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Nat Commun. 2019 May 20;10(1):2240. doi: 10.1038/s41467-019-10152-w.

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

Author information

1
Department of Pharmacology and Therapeutics and Integrated Program in Neuroscience, McGill University, Montreal, QC, H3G 1Y6, Canada.
2
Institute for Regenerative Medicine, University of Zurich, CH-8952, Schlieren, Switzerland.
3
Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081HZ, Amsterdam, The Netherlands.
4
Institut für Chemie und Biochemie, Freie Universität Berlin, 14195, Berlin, Germany.
5
SPR-MS Facility, McGill University, Montreal, QC, H3G 1Y6, Canada.
6
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081HZ, The Netherlands.
7
Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, McGill University, Montreal, H4H 1R3, QC, Canada.
8
Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada.
9
Biochemisches Institut, Christian-Albrechts-Universität-Kiel, 24118, Kiel, Germany.
10
Department of Neurology, Washington University in St. Louis, St. Louis, MO, 63110, USA.
11
Neurimmune, CH-8952, Schlieren, Switzerland.
12
Department of Pharmacology and Therapeutics and Integrated Program in Neuroscience, McGill University, Montreal, QC, H3G 1Y6, Canada. gerhard.multhaup@mcgill.ca.

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.

PMID:
31110178
PMCID:
PMC6527709
DOI:
10.1038/s41467-019-10152-w
[Indexed for MEDLINE]
Free PMC Article

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