title: Pre-amyloid oligomers budding:a metastatic mechanism of proteotoxicity.
abstract: The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology.
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Fabrizio
authors: F
authors: Bernini
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Daniele
authors: D
authors: Malferrari
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.|Cardiovascular Institute, BIDMC, Boston, MA, 02215, USA.
authors: Marcello
authors: M
authors: Pignataro
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Carlo Augusto
authors: CA
authors: Bortolotti
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Giulia
authors: G
authors: Di Rocco
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Lidia
authors: L
authors: Lancellotti
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Maria Franca
authors: MF
authors: Brigatti
authors: Department of Neurology, UTMD School of Medicine, Galveston, TX, USA.
authors: Rakez
authors: R
authors: Kayed
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Marco
authors: M
authors: Borsari
authors: Cardiovascular Institute, BIDMC, Boston, MA, 02215, USA.
authors: Federica
authors: F
authors: Del Monte
authors: Department of Chemical and Geological Sciences, University of Modena &Reggio Emilia, Modena, Italy.
authors: Elena
authors: E
authors: Castellini
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D017510:Protein Folding; D055503:Protein Multimerization; D062211:Spatio-Temporal Analysis
chemical_list: D016564:Amyloid beta-Protein Precursor; D066329:Protein Aggregates