Secondary Nucleation and Elongation Occur at Different Sites on Alzheimer's Amyloid-β Aggregates

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2019 Apr 20

PMID 31001578

Citations 74

Authors

Tom Scheidt

Urszula Lapinska

Janet R Kumita

Daniel R Whiten

David Klenerman

Mark R Wilson

Samuel I A Cohen

Sara Linse

Michele Vendruscolo

Christopher M Dobson

Tuomas P J Knowles

Paolo Arosio

Affiliations

Soon will be listed here.

Abstract

The aggregates of the Aβ peptide associated with Alzheimer's disease are able to both grow in size as well as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: the Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Aβ fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

Citing Articles

The p3 peptides (Aβ) rapidly form amyloid fibrils that cross-seed with full-length Aβ.

Tian Y, Torres-Flores A, Shang Q, Zhang H, Khursheed A, Tahirbegi B Nat Commun. 2025; 16(1):2040.

PMID: 40016209 PMC: 11868391. DOI: 10.1038/s41467-025-57341-4.

Lipid-induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation.

Sneideriene G, Gonzalez Diaz A, Adhikari S, Wei J, Michaels T, Sneideris T Proc Natl Acad Sci U S A. 2025; 122(4):e2401307122.

PMID: 39854227 PMC: 11789053. DOI: 10.1073/pnas.2401307122.

The inhibitory action of the chaperone BRICHOS against the α-Synuclein secondary nucleation pathway.

Ghosh D, Torres F, Schneider M, Ashkinadze D, Kadavath H, Fleischmann Y Nat Commun. 2024; 15(1):10038.

PMID: 39567476 PMC: 11579453. DOI: 10.1038/s41467-024-54212-2.

Accelerated Alzheimer's Aβ-42 secondary nucleation chronologically visualized on fibril surfaces.

Nirmalraj P, Bhattacharya S, Thompson D Sci Adv. 2024; 10(43):eadp5059.

PMID: 39454002 PMC: 11506133. DOI: 10.1126/sciadv.adp5059.

Single-molecule digital sizing of proteins in solution.

Krainer G, Jacquat R, Schneider M, Welsh T, Fan J, Peter Q Nat Commun. 2024; 15(1):7740.

PMID: 39231922 PMC: 11375031. DOI: 10.1038/s41467-024-50825-9.

References

Hartl F, Hayer-Hartl M . Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002; 295(5561):1852-8. DOI: 10.1126/science.1068408. View

Aprile F, Sormanni P, Perni M, Arosio P, Linse S, Knowles T . Selective targeting of primary and secondary nucleation pathways in Aβ42 aggregation using a rational antibody scanning method. Sci Adv. 2017; 3(6):e1700488. PMC: 5479649. DOI: 10.1126/sciadv.1700488. View

Narayan P, Orte A, Clarke R, Bolognesi B, Hook S, Ganzinger K . The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β(1-40) peptide. Nat Struct Mol Biol. 2011; 19(1):79-83. PMC: 4979993. DOI: 10.1038/nsmb.2191. View

Arosio P, Muller T, Rajah L, Yates E, Aprile F, Zhang Y . Microfluidic Diffusion Analysis of the Sizes and Interactions of Proteins under Native Solution Conditions. ACS Nano. 2015; 10(1):333-41. DOI: 10.1021/acsnano.5b04713. View

Arosio P, Michaels T, Linse S, Mansson C, Emanuelsson C, Presto J . Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation. Nat Commun. 2016; 7:10948. PMC: 4820785. DOI: 10.1038/ncomms10948. View

Knowles T, Waudby C, Devlin G, Cohen S, Aguzzi A, Vendruscolo M . An analytical solution to the kinetics of breakable filament assembly. Science. 2009; 326(5959):1533-7. DOI: 10.1126/science.1178250. View

Eisenberg D, Jucker M . The amyloid state of proteins in human diseases. Cell. 2012; 148(6):1188-203. PMC: 3353745. DOI: 10.1016/j.cell.2012.02.022. View

Karran E, Mercken M, De Strooper B . The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011; 10(9):698-712. DOI: 10.1038/nrd3505. View

Poon S, Rybchyn M, Carver J, Wilson M . Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000; 39(51):15953-60. DOI: 10.1021/bi002189x. View

10.

Habchi J, Arosio P, Perni M, Costa A, Yagi-Utsumi M, Joshi P . An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease. Sci Adv. 2016; 2(2):e1501244. PMC: 4758743. DOI: 10.1126/sciadv.1501244. View

11.

Mansson C, Arosio P, Hussein R, Kampinga H, Hashem R, Boelens W . Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. J Biol Chem. 2014; 289(45):31066-76. PMC: 4223311. DOI: 10.1074/jbc.M114.595124. View

12.

Hartl F, Bracher A, Hayer-Hartl M . Molecular chaperones in protein folding and proteostasis. Nature. 2011; 475(7356):324-32. DOI: 10.1038/nature10317. View

13.

Arosio P, Cukalevski R, Frohm B, Knowles T, Linse S . Quantification of the concentration of Aβ42 propagons during the lag phase by an amyloid chain reaction assay. J Am Chem Soc. 2013; 136(1):219-25. DOI: 10.1021/ja408765u. View

14.

Cohen S, Linse S, Luheshi L, Hellstrand E, White D, Rajah L . Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A. 2013; 110(24):9758-63. PMC: 3683769. DOI: 10.1073/pnas.1218402110. View

15.

Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998; 95(11):6448-53. PMC: 27787. DOI: 10.1073/pnas.95.11.6448. View

16.

Munke A, Persson J, Weiffert T, De Genst E, Meisl G, Arosio P . Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication. Proc Natl Acad Sci U S A. 2017; 114(25):6444-6449. PMC: 5488933. DOI: 10.1073/pnas.1700407114. View

17.

Beeg M, Stravalaci M, Romeo M, Carra A, Cagnotto A, Rossi A . Clusterin Binds to Aβ1-42 Oligomers with High Affinity and Interferes with Peptide Aggregation by Inhibiting Primary and Secondary Nucleation. J Biol Chem. 2016; 291(13):6958-66. PMC: 4807280. DOI: 10.1074/jbc.M115.689539. View

18.

Chiti F, Dobson C . Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu Rev Biochem. 2017; 86:27-68. DOI: 10.1146/annurev-biochem-061516-045115. View

19.

Wyatt A, Yerbury J, Ecroyd H, Wilson M . Extracellular chaperones and proteostasis. Annu Rev Biochem. 2013; 82:295-322. DOI: 10.1146/annurev-biochem-072711-163904. View

20.

Michaels T, Saric A, Habchi J, Chia S, Meisl G, Vendruscolo M . Chemical Kinetics for Bridging Molecular Mechanisms and Macroscopic Measurements of Amyloid Fibril Formation. Annu Rev Phys Chem. 2018; 69:273-298. DOI: 10.1146/annurev-physchem-050317-021322. View