Ultrastructural evidence for self-replication of alzheimer-associated Aβ42 amyloid along the sides of fibrils

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Ultrastructural evidence for self-replication of alzheimer-associated Aβ42 amyloid along the sides of fibrils. / Tornquist, Mattias; Cukalevski, Risto; Weininger, Ulrich; Meisl, Georg; Knowles, Tuomas P.J.; Leiding, Thom; Malmendal, Anders; Akke, Mikael; Linse, Sara.

I: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Nr. 21, 26.05.2020, s. 11265-11273.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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T1 - Ultrastructural evidence for self-replication of alzheimer-associated Aβ42 amyloid along the sides of fibrils

AU - Tornquist, Mattias

AU - Cukalevski, Risto

AU - Weininger, Ulrich

AU - Meisl, Georg

AU - Knowles, Tuomas P.J.

AU - Leiding, Thom

AU - Malmendal, Anders

AU - Akke, Mikael

AU - Linse, Sara

PY - 2020/5/26

Y1 - 2020/5/26

N2 - The nucleation of Alzheimer-associated Aβ peptide monomers can be catalyzed by preexisting Aβ fibrils. This leads to autocatalytic amplification of aggregate mass and underlies self-replication and generation of toxic oligomers associated with several neurodegenerative diseases. However, the nature of the interactions between the monomeric species and the fibrils during this key process, and indeed the ultrastructural localization of the interaction sites have remained elusive. Here we used NMR and optical spectroscopy to identify conditions that enable the capture of transient species during the aggregation and secondary nucleation of the Aβ42 peptide. Cryo-electron microscopy (cryo-EM) images show that new aggregates protrude from the entire length of the progenitor fibril. These protrusions are morphologically distinct from the wellordered fibrils dominating at the end of the aggregation process. The data provide direct evidence that self-replication through secondary nucleation occurs along the sides of fibrils, which become heavily decorated under the current solution conditions (14 μM Aβ42, 20 mM sodium phosphate, 200 μM EDTA, pH 6.8).

AB - The nucleation of Alzheimer-associated Aβ peptide monomers can be catalyzed by preexisting Aβ fibrils. This leads to autocatalytic amplification of aggregate mass and underlies self-replication and generation of toxic oligomers associated with several neurodegenerative diseases. However, the nature of the interactions between the monomeric species and the fibrils during this key process, and indeed the ultrastructural localization of the interaction sites have remained elusive. Here we used NMR and optical spectroscopy to identify conditions that enable the capture of transient species during the aggregation and secondary nucleation of the Aβ42 peptide. Cryo-electron microscopy (cryo-EM) images show that new aggregates protrude from the entire length of the progenitor fibril. These protrusions are morphologically distinct from the wellordered fibrils dominating at the end of the aggregation process. The data provide direct evidence that self-replication through secondary nucleation occurs along the sides of fibrils, which become heavily decorated under the current solution conditions (14 μM Aβ42, 20 mM sodium phosphate, 200 μM EDTA, pH 6.8).

KW - Aggregation mechanism

KW - Amyloidosis

KW - Fibril formation

KW - Neurodegeneration

KW - Self-assembly

UR - http://www.scopus.com/inward/record.url?scp=85085467631&partnerID=8YFLogxK

U2 - 10.1073/pnas.1918481117

DO - 10.1073/pnas.1918481117

M3 - Article

C2 - 32439711

AN - SCOPUS:85085467631

VL - 117

SP - 11265

EP - 11273

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 21

ER -