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Cellular prion protein acts as mediator of amyloid beta uptake by caveolin-1 causing cellular dysfunctions in vitro
Angela da Silva Correia1, Matthias Schmitz1, Anna-Lisa Fischer1
1Department of Neurology, University Medical Center and the German Center for Neurodegenerative Diseases (DZNE), Georg-August University, Goettingen, Germany.
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.
Insights
Cellular prion protein (PrPC) worsens Alzheimer's disease (AD) in mice by increasing amyloid beta (Aβ) plaques and reducing lifespan. Caveolin-1 (Cav-1) also plays a role in Aβ uptake and plaque load.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Cellular prion protein (PrPC) is linked to amyloid beta (Aβ)-induced toxicity in Alzheimer's disease (AD).
- The exact molecular mechanisms of PrPC involvement in AD pathogenesis remain unclear.
- Investigating PrPC and its interaction with Aβ is crucial for understanding AD progression.
Purpose of the Study:
- To elucidate the role of PrPC in Alzheimer's disease pathogenesis.
- To investigate the impact of PrPC on amyloid beta (Aβ) levels and plaque burden.
- To explore the interaction between PrPC, Aβ, and Caveolin-1 (Cav-1) in AD.
Main Methods:
- Generation of double transgenic mice (Prnp knockout crossed with 5xFAD mice).
- Whole brain tissue analysis using light-sheet microscopy.
- In vitro studies using PrPC-overexpressing cells and surface-plasmon resonance (SPR) to assess protein interactions.
Main Results:
- PrPC levels correlated with reduced lifespan, cognitive, and motor function in 5xFAD mice.
- PrPC ablation disconnected behavioral deficits from Aβ levels and influenced Aβ-plaque burden.
- Caveolin-1 (Cav-1) knockout neurons showed reduced intracellular Aβ-oligomer (Aβo) uptake.
Conclusions:
- PrPC expression negatively impacts lifespan and behavior in 5xFAD mice.
- PrPC exacerbates Aβ levels and plaque load, while Cav-1 modulates intracellular Aβ levels.
- PrPC and Cav-1 are key modulators of intracellular Aβ levels and Aβ-plaque load in AD.
