title: Abeta42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Abeta42 species.
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.
authors.affiliation: From the Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute.
authors.forename: Asad
authors.initials: A
authors.lastname: Jan
authors.affiliation: AC Immune, PSE-B, and.
authors.forename: Oskar
authors.initials: O
authors.lastname: Adolfsson
authors.affiliation: Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Allaman
authors.affiliation: AC Immune, PSE-B, and.
authors.forename: Anna-Lucia
authors.initials: AL
authors.lastname: Buccarello
authors.affiliation: Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: AC Immune, PSE-B, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: AC Immune, PSE-B, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.affiliation: From the Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute,. Electronic address: hilal.lashuel@epfl.ch.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)