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Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice.

Ruiz-Riquelme, A; Mao, A; Barghash, MM; Lau, HHC; Stuart, E; Kovacs, GG; Nilsson, KPR; ... Watts, JC; + view all (2021) Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice. Acta Neuropathologica Communications , 9 (1) , Article 83. 10.1186/s40478-021-01187-6. Green open access

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Abstract

When injected into genetically modified mice, aggregates of the amyloid-β (Aβ) peptide from the brains of Alzheimer's disease (AD) patients or transgenic AD mouse models seed cerebral Aβ deposition in a prion-like fashion. Within the brain, Aβ exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal Aβ variants to the seeding behavior of Aβ aggregates remains unknown. Here, we have investigated the relative seeding activities of Aβ aggregates composed exclusively of recombinant Aβ38, Aβ40, Aβ42, or Aβ43. Cerebral Aβ42 levels were not increased in AppNL-F knock-in mice injected with Aβ38 or Aβ40 aggregates and were only increased in a subset of mice injected with Aβ42 aggregates. In contrast, significant accumulation of Aβ42 was observed in the brains of all mice inoculated with Aβ43 aggregates, and the extent of Aβ42 induction was comparable to that in mice injected with brain-derived Aβ seeds. Mice inoculated with Aβ43 aggregates exhibited a distinct pattern of cerebral Aβ pathology compared to mice injected with brain-derived Aβ aggregates, suggesting that recombinant Aβ43 may polymerize into a unique strain. Our results indicate that aggregates containing longer Aβ C-terminal variants are more potent inducers of cerebral Aβ deposition and highlight the potential role of Aβ43 seeds as a crucial factor in the initial stages of Aβ pathology in AD.

Type: Article
Title: Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s40478-021-01187-6
Publisher version: https://doi.org/10.1186/s40478-021-01187-6
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
Keywords: Alzheimer’s disease, Amyloid-β, Knock-in mice, Prion-like propagation, Strains
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 Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10128446
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