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Cellular prion protein acts as mediator of amyloid beta uptake by caveolin-1 causing cellular dysfunctions in vitro and in vivo

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

Abstract

© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.INTRODUCTION: Cellular prion protein (PrPC) was implicated in amyloid beta (Aβ)-induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear. METHODS: Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light-sheet microscopy was used for whole brain tissue analyses. PrPC-overexpressing cells were developed for in vitro studies, and microscopy was used to assess co-localization of proteins of interest. Surface-plasmon resonance (SPR) was used to investigate protein-binding characteristics. RESULTS: In vivo, PrPClevels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from Aβ levels. Light-sheet microscopy showed that PrPC influenced Aβ-plaque burden but not the distribution of those plaques. Interestingly, caveolin-1 (Cav-1) KO neurons significantly reduced intracellular Aβ-oligomer (Aβo) uptake when compared to wild-type neurons. DISCUSSION: The findings shed new light on the relevance of intracellular Aβo, suggesting that PrPC and Cav-1 modulate intracellular Aβ levels and the Aβ-plaque load. Highlights: PrPC expression adversely affects lifespan and behavior in 5xFAD mice. PrPC increases Aβ1-40 and Aβ1-42 levels and Aβ-plaque load in 5xFAD mice. Cav-1 interacts with both PrPC and Aβ peptides. Knocking out Cav-1 leads to a significant reduction in intracellular Aβ levels.

Publication metadata

Author(s): da Silva Correia A, Schmitz M, Fischer A-L, da Silva Correia S, Simonetti FL, Saher G, Goya-Maldonado R, Arora AS, Fischer A, Outeiro TF, Zerr I

Publication type: Article

Publication status: Published

Journal: Alzheimer's and Dementia

Year: 2024

Volume: 20

Issue: 10

Pages: 6776-6792

Print publication date: 01/10/2024

Online publication date: 30/08/2024

Acceptance date: 10/06/2024

Date deposited: 09/09/2024

ISSN (print): 1552-5260

ISSN (electronic): 1552-5279

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/alz.14120

DOI: 10.1002/alz.14120

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