Journal
FEBS LETTERS
Volume 594, Issue 21, Pages 3490-3503Publisher
WILEY
DOI: 10.1002/1873-3468.13919
Keywords
Alzheimer's disease; amyloid fibril; neurotoxicity; oligomer
Funding
- MRC [MR/K022105/1] Funding Source: UKRI
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Amyloid fibrils found in plaques in Alzheimer's disease (AD) brains are composed of amyloid-beta peptides. Oligomeric amyloid-beta 1-42 (A beta 42) is thought to play a critical role in neurodegeneration in AD. Here, we determine how size and conformation affect neurotoxicity and internalisation of A beta 42 assemblies using biophysical methods, immunoblotting, toxicity assays and live-cell imaging. We report significant cytotoxicity of A beta 42 oligomers and their internalisation into neurons. In contrast, A beta 42 fibrils show reduced internalisation and no toxicity. Sonicating A beta 42 fibrils generates species similar in size to oligomers but remains nontoxic. The results suggest that A beta 42 oligomers have unique properties that underlie their neurotoxic potential. Furthermore, we show that incubating cells with A beta 42 oligomers for 24 h is sufficient to trigger irreversible neurotoxicity.
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