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

TitleAβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.
Publication TypeJournal Article
Year of Publication2019
AuthorsLiebsch F, Kulic L, Teunissen C, Shobo A, Ulku I, Engelschalt V, Hancock MA, van der Flier WM, Kunach P, Rosa-Neto P, Scheltens P, Poirier J, Saftig P, Bateman RJ, Breitner J, Hock C, Multhaup G
JournalNat Commun
Volume10
Issue1
Pagination2240
Date Published2019 05 20
ISSN2041-1723
KeywordsAged, Alzheimer Disease, Amyloid beta-Peptides, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Biomarkers, Brain, Cell Line, Tumor, Cognitive Dysfunction, Cohort Studies, Disease Progression, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Peptide Fragments, Proteolysis, Rats, Rats, Sprague-Dawley
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.

DOI10.1038/s41467-019-10152-w
Alternate JournalNat Commun
PubMed ID31110178
PubMed Central IDPMC6527709

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