Structure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface

Rebeccah A. Warmack, David R. Boyer, Chih-Te Zee, Logan S. Richards, Michael R. Sawaya, Duilio Cascio, Tamir Gonen, David S. Eisenberg and Steven G. Clarke ()
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Rebeccah A. Warmack: University of California, Los Angeles
David R. Boyer: University of California, Los Angeles
Chih-Te Zee: University of California, Los Angeles
Logan S. Richards: University of California, Los Angeles
Michael R. Sawaya: University of California, Los Angeles
Duilio Cascio: University of California, Los Angeles
Tamir Gonen: University of California, Los Angeles
David S. Eisenberg: University of California, Los Angeles
Steven G. Clarke: University of California, Los Angeles

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer’s disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20–34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20–34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.

Date: 2019
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DOI: 10.1038/s41467-019-11183-z

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