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

Purro, Silvia A; Farmer, Michael; Noble, Elizabeth; Sarell, Claire J; Powell, Megan; Yip, Daniel; Giggins, Lauren; ... Collinge, John; + view all (2023) Two mouse models of Alzheimer's disease accumulate amyloid at different rates and have distinct Aβ oligomer profiles unaltered by ablation of cellular prion protein. PLoS One , 18 (11) , Article e0294465. 10.1371/journal.pone.0294465. Green open access

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Abstract

Oligomers formed from monomers of the amyloid β-protein (Aβ) 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 (PrPC) is now an established receptor for Aβ oligomers. However, studies of the Aβ-PrPC 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 PrPC 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 PrPC, and were recognised by the OC antibody which distinguishes parallel, in register fibrils. On the other hand, J20 mice had a lower level of Aβ oligomers, which did not interact with PrPC when tested in vitro and were OC-negative. These results suggest the two mouse models produce diverse Aβ assemblies that could interact with different targets, highlighting the necessity to characterise the conformation of the Aβ 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 Aβ toxicity mediated by PrPC.

Type: Article
Title: Two mouse models of Alzheimer's disease accumulate amyloid at different rates and have distinct Aβ oligomer profiles unaltered by ablation of cellular prion protein
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0294465
Publisher version: https://doi.org/10.1371/journal.pone.0294465
Language: English
Additional information: © 2023 Purro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Humans, Mice, Animals, Alzheimer Disease, Amyloid beta-Peptides, Prion Proteins, Longitudinal Studies, PrPC Proteins, Prions, Mice, Transgenic
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10182407
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