Pre-amyloid oligomers budding: A metastatic mechanism of proteotoxicity

Fabrizio Bernini, Daniele Malferrari, Marcello Pignataro, Carlo Augusto Bortolotti, Giulia Di Rocco, Lidia Lancellotti, Maria Franca Brigatti, Rakez Kayed, Marco Borsari, Federica Del Monte, Elena Castellini

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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.

Original languageEnglish (US)
Article number35865
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 24 2016

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Cite this

Bernini, F., Malferrari, D., Pignataro, M., Bortolotti, C. A., Di Rocco, G., Lancellotti, L., Brigatti, M. F., Kayed, R., Borsari, M., Del Monte, F., & Castellini, E. (2016). Pre-amyloid oligomers budding: A metastatic mechanism of proteotoxicity. Scientific reports, 6, [35865]. https://doi.org/10.1038/srep35865