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

Author:

da Silva Correia Angela1,Schmitz Matthias1,Fischer Anna‐Lisa1,da Silva Correia Susana1,Simonetti Franco L.2,Saher Gesine3,Goya‐Maldonado Roberto4,Arora Amandeep Singh5,Fischer Andre67,Outeiro Tiago F.891011,Zerr Inga1

Affiliation:

1. Department of Neurology University Medical Center and the German Center for Neurodegenerative Diseases (DZNE) Georg‐August University Goettingen Germany

2. Fundación Instituto Leloir Buenos Aires Argentina

3. Department of Neurogenetics Max Planck Institute for Multidisciplinary Sciences Goettingen Germany

4. Laboratory of Systems Neuroscience and Imaging in Psychiatry (SNIP‐Lab) Department of Psychiatry and Psychotherapy University Medical Center Goettingen (UMG) Goettingen Germany

5. Texas Therapeutics Institute Brown Foundation Institute of Molecular Medicine University of Texas Health Science Center at Houston Houston Texas USA

6. Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

7. Department for Systems Medicine and Epigenetics in Neurodegenerative Diseases German Center for Neurodegenerative Diseases (DZNE) Goettingen Goettingen Germany

8. Department of Experimental Neurodegeneration Center for Nanoscale Microscopy and Molecular Physiology of the Brain Center for Biostructural Imaging of Neurodegeneration University Medical Center Goettingen Goettingen Germany

9. Max Planck Institute for Multidisciplinary Sciences Goettingen Germany

10. Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle UK

11. Scientific employee with an honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Goettingen Germany

Abstract

AbstractINTRODUCTIONCellular 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.METHODSDouble 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.RESULTSIn vivo, PrPlevels 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.DISCUSSIONThe 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.

Funder

Alzheimer Forschung Initiative

Publisher

Wiley

Reference60 articles.

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