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

Liebsch, Filip, Kulic, Luka, Teunissen, Charlotte, Shobo, Adeola, Ulku, Irem, Engelschalt, Vivienne, Hancock, Mark A., van der Flier, Wiesje M., Kunach, Peter, Rosa-Neto, Pedro, Scheltens, Philip, Poirier, Judes, Saftig, Paul, Bateman, Randall J., Breitner, John, Hock, Christoph, Multhaup, Gerhard·2019·Nature Communications
DOI 10.1038/s41467-019-10152-wPMC PMC6527709
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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.

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Metadata

Authors
Liebsch, F., Kulic, L., Teunissen, C., Shobo, A., Ulku, I., Engelschalt, V., Hancock, M. A., van der Flier, W. M., Kunach, P., Rosa-Neto, P., Scheltens, P., Poirier, J., Saftig, P., Bateman, R. J., Breitner, J., Hock, C., & Multhaup, G.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-05-20
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-10152-w
PMC
PMC6527709
Cited by
68
References
12
Language
en
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