Amyloid-beta oligomer-Prion protein complex (AβO-PrPC)

The interaction between amyloid-beta (Aβ) oligomers and the cellular prion protein (PrPC) at the neuronal lipid membrane is a critical pathological event in Alzheimer's disease. PrPC serves as a high-affinity cell-surface receptor for soluble Aβ oligomers, which are considered the primary neurotoxic species in the brain (Laurén et al., Nature, 2009). This binding occurs predominantly within cholesterol-rich lipid rafts, which facilitate the assembly of a transmembrane signaling complex. Once bound, the Aβ-PrPC complex recruits and activates metabotropic glutamate receptor 5 (mGluR5) and the intracellular tyrosine kinase Fyn (Um et al., Neuron, 2013). This signaling cascade leads to the hyperphosphorylation of Tau protein and the retraction of dendritic spines, resulting in synaptic failure and cognitive decline. Therapeutic interventions aim to disrupt this interaction or inhibit the downstream signaling components to preserve cognitive function. Small molecules like BMS-984923 are being developed to selectively block the pathological signaling of this complex without affecting normal neurotransmission. Targeting the Aβ-PrPC interface offers a potential way to mitigate neurotoxicity by addressing the specific signaling pathway that links amyloid pathology to tau-mediated neurodegeneration.

Other names

Aβ-PrP complexAmyloid-beta/Prion protein interactionAβO-PrPC signaling complexCellular prion protein-amyloid beta oligomer complexAβ-PrPC-mGluR5 complex

Disruption of amyloid-beta oligomer binding to cellular prion protein or inhibition of downstream signaling through mGluR5 and Fyn kinase to prevent synaptic loss.