Cellular Prion Protein Acts As Mediator of Amyloid Beta Uptake by Caveolin-1 Causing Cellular Dysfunctions In Vitro and In Vivo

Authors

• Angela da Silva Correia
• Matthias Schmitz
• Anna-Lisa Fischer
• Susana da Silva Correia
• Franco L Simonetti
• Gesine Saher
• Roberto Goya-Maldonado
• Amandeep Singh Arora
• Andre Fischer
• Tiago F Outeiro
• Inga Zerr

Language

English

Publication Date

10-1-2024

Journal

Alzheimer's & Dementia Journal

DOI

10.1002/alz.14120

PMID

39212313

PMCID

PMC11485400

PubMedCentral® Posted Date

8-30-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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, PrPC levels 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.

Keywords

Animals, Humans, Mice, Alzheimer Disease, Amyloid beta-Peptides, Brain, Caveolin 1, Disease Models, Animal, Mice, Knockout, Mice, Transgenic, Neurons, Plaque, Amyloid, Prion Proteins, PrPC Proteins, Alzheimer's disease, amyloid beta, caveolin, cellular prion protein

Published Open-Access

yes

Recommended Citation

da Silva Correia, Angela; Schmitz, Matthias; Fischer, Anna-Lisa; et al., "Cellular Prion Protein Acts As Mediator of Amyloid Beta Uptake by Caveolin-1 Causing Cellular Dysfunctions In Vitro and In Vivo" (2024). Faculty, Staff and Student Publications. 3471.
https://digitalcommons.library.tmc.edu/uthmed_docs/3471