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  • Title: Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5-42.
    Author: Weiffert T, Meisl G, Flagmeier P, De S, Dunning CJR, Frohm B, Zetterberg H, Blennow K, Portelius E, Klenerman D, Dobson CM, Knowles TPJ, Linse S.
    Journal: ACS Chem Neurosci; 2019 May 15; 10(5):2374-2384. PubMed ID: 30793584.
    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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