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Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5-42.

Journal article
Authors Tanja Weiffert
Georg Meisl
Patrick Flagmeier
Suman De
Christopher J R Dunning
Birgitta Frohm
Henrik Zetterberg
Kaj Blennow
Erik Portelius
David Klenerman
Christopher M Dobson
Tuomas P J Knowles
Published in ACS chemical neuroscience
Volume 10
Issue 5
Pages 2374-2384
ISSN 1948-7193
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 2374-2384
Language en
Links dx.doi.org/10.1021/acschemneuro.8b0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Neurochemistry

Abstract

Aggregation of the amyloid-β (Aβ) peptide into plaques is believed to play a crucial role in Alzheimer's disease. Amyloid plaques consist of fibrils of full length Aβ peptides as well as N-terminally truncated species. β-Site amyloid precursor protein-cleaving enzyme (BACE1) cleaves amyloid precursor protein in the first step in Aβ peptide production and is an attractive therapeutic target to limit Aβ generation. Inhibition of BACE1, however, induces a unique pattern of Aβ peptides with increased levels of N-terminally truncated Aβ peptides starting at position 5 (Aβ5-X), indicating that these peptides are generated through a BACE1-independent pathway. Here we elucidate the aggregation mechanism of Aβ5-42 and its influence on full-length Aβ42. We find that, compared to Aβ42, Aβ5-42 is more aggregation prone and displays enhanced nucleation rates. Aβ5-42 oligomers cause nonspecific membrane disruption to similar extent as Aβ42 but appear at earlier time points in the aggregation reaction. Noteworthy, this implies similar toxicity of Aβ42 and Aβ5-42 and the toxic species are generated faster by Aβ5-42. The increased rate of secondary nucleation on the surface of existing fibrils originates from a higher affinity of Aβ5-42 monomers for fibrils, as compared to Aβ42: an effect that may be related to the reduced net charge of Aβ5-42. Moreover, Aβ5-42 and Aβ42 peptides coaggregate into heteromolecular fibrils and either species can elongate existing Aβ42 or Aβ5-42 fibrils but Aβ42 fibrils are more catalytic than Aβ5-42 fibrils. Our findings highlight the importance of the N-terminus for surface-catalyzed nucleation and thus the production of toxic oligomers.

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