cAMP-induced decrease in cell-surface laminin receptor and cellular prion protein attenuates amyloid-β uptake and
Rayudu Gopalakrishna1, Charlotte Y Lin1, Andrew Oh1
1Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
FEBS Letters
|August 16, 2022
Summary
Cyclic AMP (cAMP) protects neuronal cells from amyloid-β oligomer (AβO) toxicity by reducing cell-surface prion protein (PrPC) and laminin receptor (67LR) levels. This mechanism inhibits AβO uptake and subsequent cell death.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Amyloid-β oligomers (AβO) are implicated in neuronal dysfunction.
- AβO bind to cellular prion protein (PrPC), forming complexes with co-receptors like the laminin receptor (67LR).
Purpose of the Study:
- To investigate the role of 67LR as a co-receptor in AβO uptake and toxicity.
- To explore the neuroprotective effects of cAMP-elevating agents against AβO-induced neuronal cell death.
Main Methods:
- Utilized Neuroscreen-1 cells to study AβO-PrPC interactions.
- Administered pharmacological and physiological cAMP-elevating agents.
- Assessed cell-surface PrPC and 67LR levels, AβO uptake, and neuronal cell death.
- Investigated the involvement of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac).
Main Results:
- 67LR was identified as the primary co-receptor for AβO uptake and AβO-induced cell death in Neuroscreen-1 cells.
- cAMP-elevating agents significantly reduced cell-surface PrPC and 67LR expression.
- Reduced co-receptor levels attenuated AβO uptake and subsequent neuronal cell death.
- The protective effects of cAMP were dependent on PKA activation but independent of Epac.
Conclusions:
- cAMP-elevating agents confer neuroprotection against AβO toxicity.
- This protection is mediated by the downregulation of cell-surface PrPC and 67LR, thereby inhibiting AβO binding and cellular entry.
- Targeting cAMP signaling pathways may represent a therapeutic strategy for AβO-related neurodegenerative diseases.
