Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms.

Autor: De S; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. sd730@cam.ac.uk., Wirthensohn DC; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Flagmeier P; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Hughes C; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK., Aprile FA; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Ruggeri FS; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Whiten DR; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Emin D; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Xia Z; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Varela JA; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Sormanni P; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Kundel F; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Knowles TPJ; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Cavendish Laboratory, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 1HE, UK., Dobson CM; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK., Bryant C; Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK., Vendruscolo M; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. mv245@cam.ac.uk.; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. mv245@cam.ac.uk., Klenerman D; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. dk10012@cam.ac.uk.; UK Dementia Research Institute, University of Cambridge, Cambridge, CB2 0XY, UK. dk10012@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Apr 04; Vol. 10 (1), pp. 1541. Date of Electronic Publication: 2019 Apr 04.
DOI: 10.1038/s41467-019-09477-3
Abstrakt: Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.
Databáze: MEDLINE