Two mouse models of Alzheimer's disease accumulate amyloid at different rates and have distinct A[beta] oligomer profiles unaltered by ablation of cellular prion protein

Oligomers formed from monomers of the amyloid [beta]-protein (A[beta]) are thought to be central to the pathogenesis of Alzheimer's disease (AD). Unsurprisingly for a complex disease, current mouse models of AD fail to fully mimic the clinical disease in humans. Moreover, results obtained in a...

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Published in:PloS one 2023-11, Vol.18 (11), p.e0294465
Main Authors: Purro, Silvia A, Farmer, Michael, Noble, Elizabeth, Sarell, Claire J, Powell, Megan, Yip, Daniel, Giggins, Lauren, Zakka, Leila, Thomas, David X, Farrow, Mark, Nicoll, Andrew J, Walsh, Dominic, Collinge, John
Format: Article
Language:English
Subjects:
Advertising executives
Alzheimer's disease
Amyloid beta-protein
Antibodies
Care and treatment
Diagnosis
Ethylenediaminetetraacetic acid
Health aspects
Oligomers
Prions
Viral antibodies
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Summary:Oligomers formed from monomers of the amyloid [beta]-protein (A[beta]) are thought to be central to the pathogenesis of Alzheimer's disease (AD). Unsurprisingly for a complex disease, current mouse models of AD fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproduced in a different model. Cellular prion protein (PrP.sup.C) is now an established receptor for A[beta] oligomers. However, studies of the A[beta]-PrP.sup.C interaction in different mouse models have yielded contradictory results. Here we performed a longitudinal study assessing a range of biochemical and histological features in the commonly used J20 and APP-PS1 mouse models. Our analysis demonstrated that PrP.sup.C ablation had no effect on amyloid accumulation or oligomer production. However, we found that APP-PS1 mice had higher levels of oligomers, that these could bind to recombinant PrP.sup.C, and were recognised by the OC antibody which distinguishes parallel, in register fibrils. On the other hand, J20 mice had a lower level of A[beta] oligomers, which did not interact with PrP.sup.C when tested in vitro and were OC-negative. These results suggest the two mouse models produce diverse A[beta] assemblies that could interact with different targets, highlighting the necessity to characterise the conformation of the A[beta] oligomers concomitantly with the toxic cascade elicited by them. Our results provide an explanation for the apparent contradictory results found in APP-PS1 mice and the J20 mouse line in regards to A[beta] toxicity mediated by PrP.sup.C.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0294465