Amyloid-beta oligomer and cellular prion protein membrane interaction (Aβ-PrPC interaction)

The interaction between Amyloid-beta (Aβ) oligomers and the cellular prion protein (PrPC) at the neuronal membrane is a critical pathological event in Alzheimer's disease (Laurén et al., Nature, 2009). PrPC serves as a high-affinity cell-surface receptor for soluble Aβ oligomers, which are considered the most neurotoxic forms of the peptide (Um et al., Neuron, 2013). This binding event occurs primarily within lipid rafts and triggers a transmembrane signaling cascade involving metabotropic glutamate receptor 5 (mGluR5) and the intracellular tyrosine kinase Fyn (Haas et al., Nature Communications, 2016). Activation of this pathway leads to the phosphorylation of N-methyl-D-aspartate (NMDA) receptors, resulting in synaptic dysfunction, dendritic spine loss, and eventually neuronal death (Smith et al., JBC, 2019). Therapeutic strategies targeting this interaction include monoclonal antibodies like PRN100 that block the Aβ-binding site on PrPC, and small molecules like BMS-984923 designed to inhibit the downstream mGluR5 signaling axis (Nygaard et al., Biological Psychiatry, 2015; ClinicalTrials.gov NCT04805060). Understanding the membrane environment is essential, as lipid composition significantly influences the affinity and aggregation state of the Aβ-PrPC complex.

Other names

Aβ-PrPC complexAmyloid-beta binding to cellular prion proteinPrP-Aβ oligomer interactionPrPC-mGluR5-Aβ signaling complexAmyloid-beta and PrP peptide/membrane interaction

Inhibition of Amyloid-beta oligomer binding to cellular prion protein, neutralization of Amyloid-beta aggregates, or antagonism of downstream signaling components like mGluR5 to prevent synaptic toxicity (Laurén et al., Nature, 2009; Um et al., Neuron, 2013).