Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species

Asad Jan, Oskar Adolfsson, Igor Allaman, Anna Lucia Buccarello, Pierre J. Magistretti, Andrea Pfeifer, Andreas Muhs, Hilal A. Lashuel

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

The identification of toxic Aβ species and/or the process of their formation is crucial for understanding the mechanism(s) of Aβ neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of Aβ toxicity, we developed different procedures to isolate Aβ species of defined size and morphology distribution, and we investigated their toxicity in different cell lines and primary neurons. We observed that crude Aβ42 preparations, containing a monomeric and heterogeneous mixture of Aβ42 oligomers, were more toxic than purified monomeric, protofibrillar fractions, or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric Aβ42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity, whereas reintroduction of monomeric Aβ42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric Aβ42 from these preparations, using insulin-degrading enzyme, reversed the toxicity of Aβ42 protofibrils. Together, our findings demonstrate that Aβ42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation, which depends on the presence of monomeric Aβ42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease, provide novel insight into mechanisms of Aβ protofibril toxicity, and important implications for designing anti-amyloid therapies.

Original languageEnglish
Pages (from-to)8585-8596
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
Publication statusPublished - 11 Mar 2011
Externally publishedYes

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Amyloid
Polymerization
Toxicity
Aptitude
Poisons
Alzheimer Disease
Insulysin
Neurons
Cell Line
Therapeutics
Oligomers
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Jan, A., Adolfsson, O., Allaman, I., Buccarello, A. L., Magistretti, P. J., Pfeifer, A., ... Lashuel, H. A. (2011). Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. Journal of Biological Chemistry, 286(10), 8585-8596. https://doi.org/10.1074/jbc.M110.172411

Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. / Jan, Asad; Adolfsson, Oskar; Allaman, Igor; Buccarello, Anna Lucia; Magistretti, Pierre J.; Pfeifer, Andrea; Muhs, Andreas; Lashuel, Hilal A.

In: Journal of Biological Chemistry, Vol. 286, No. 10, 11.03.2011, p. 8585-8596.

Research output: Contribution to journalArticle

Jan, A, Adolfsson, O, Allaman, I, Buccarello, AL, Magistretti, PJ, Pfeifer, A, Muhs, A & Lashuel, HA 2011, 'Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species', Journal of Biological Chemistry, vol. 286, no. 10, pp. 8585-8596. https://doi.org/10.1074/jbc.M110.172411
Jan, Asad ; Adolfsson, Oskar ; Allaman, Igor ; Buccarello, Anna Lucia ; Magistretti, Pierre J. ; Pfeifer, Andrea ; Muhs, Andreas ; Lashuel, Hilal A. / Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 10. pp. 8585-8596.
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