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Rodina, N. ; Hornung, S.* ; Sarkar, R. ; Suladze, S.* ; Peters, C.* ; Schmid, P.W.N.* ; Niu, Z.* ; Haslbeck, M.* ; Buchner, J.* ; Kapurniotu, A.* ; Reif, B.

Modulation of Alzheimer's disease Aβ40 fibril polymorphism by the small heat shock protein αB-crystallin.

J. Am. Chem. Soc. 146, 19077–19087 (2024)
DOI PMC
Open Access Green: Postprint online verfügbar 07/2025
Deposition of amyloid plaques in the brains of Alzheimer's disease (AD) patients is a hallmark of the disease. AD plaques consist primarily of the beta-amyloid (Aβ) peptide but can contain other factors such as lipids, proteoglycans, and chaperones. So far, it is unclear how the cellular environment modulates fibril polymorphism and how differences in fibril structure affect cell viability. The small heat-shock protein (sHSP) alpha-B-Crystallin (αBC) is abundant in brains of AD patients, and colocalizes with Aβ amyloid plaques. Using solid-state NMR spectroscopy, we show that the Aβ40 fibril seed structure is not replicated in the presence of the sHSP. αBC prevents the generation of a compact fibril structure and leads to the formation of a new polymorph with a dynamic N-terminus. We find that the N-terminal fuzzy coat and the stability of the C-terminal residues in the Aβ40 fibril core affect the chemical and thermodynamic stability of the fibrils and influence their seeding capacity. We believe that our results yield a better understanding of how sHSP, such as αBC, that are part of the cellular environment, can affect fibril structures related to cell degeneration in amyloid diseases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Beta-amyloid Peptide; Secondary Nucleation; Thioflavin-t; Self-propagation; Structural Basis; Aggregation; Binding; Oligomers; Inhibition; Neurodegeneration
ISSN (print) / ISBN 0002-7863
e-ISSN 1520-5126
Zeitschrift Journal of the American Chemical Society
Quellenangaben Band: 146, Heft: 28, Seiten: 19077–19087 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen Helmholtz-Gemeinschaft
German Research Foundation DFG