%0 Journal Article
%T Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated A汕42 Species A汕5每42
%J -
%D 2019
%R https://doi.org/10.1021/acschemneuro.8b00676
%X Aggregation of the amyloid-汕 (A汕) peptide into plaques is believed to play a crucial role in Alzheimer＊s disease. Amyloid plaques consist of fibrils of full length A汕 peptides as well as N-terminally truncated species. 汕-Site amyloid precursor protein-cleaving enzyme (BACE1) cleaves amyloid precursor protein in the first step in A汕 peptide production and is an attractive therapeutic target to limit A汕 generation. Inhibition of BACE1, however, induces a unique pattern of A汕 peptides with increased levels of N-terminally truncated A汕 peptides starting at position 5 (A汕5-X), indicating that these peptides are generated through a BACE1-independent pathway. Here we elucidate the aggregation mechanism of A汕5每42 and its influence on full-length A汕42. We find that, compared to A汕42, A汕5每42 is more aggregation prone and displays enhanced nucleation rates. A汕5每42 oligomers cause nonspecific membrane disruption to similar extent as A汕42 but appear at earlier time points in the aggregation reaction. Noteworthy, this implies similar toxicity of A汕42 and A汕5每42 and the toxic species are generated faster by A汕5每42. The increased rate of secondary nucleation on the surface of existing fibrils originates from a higher affinity of A汕5每42 monomers for fibrils, as compared to A汕42: an effect that may be related to the reduced net charge of A汕5每42. Moreover, A汕5每42 and A汕42 peptides coaggregate into heteromolecular fibrils and either species can elongate existing A汕42 or A汕5每42 fibrils but A汕42 fibrils are more catalytic than A汕5每42 fibrils. Our findings highlight the importance of the N-terminus for surface-catalyzed nucleation and thus the production of toxic oligomers
%U https://pubs.acs.org/doi/10.1021/acschemneuro.8b00676