Amyloid-beta oligomer and cellular prion protein hetero-assembly interface (Aβo-PrPC interface)

The Amyloid-beta oligomer and cellular prion protein (PrPC) hetero-assembly interface is a pathological protein-protein interaction site critical to the neurotoxic cascade in Alzheimer's disease [3, 9]. Soluble amyloid-beta oligomers (Aβo) bind with high affinity to the N-terminal domain of membrane-anchored PrPC, forming a complex that subsequently recruits the metabotropic glutamate receptor 5 (mGluR5) [12, 17]. This assembly triggers the activation of intracellular Fyn kinase, leading to the phosphorylation of NMDA receptors and the subsequent loss of synaptic spines and dendritic integrity [3, 11]. Unlike insoluble amyloid plaques, these soluble oligomeric assemblies are directly linked to synaptic dysfunction and cognitive impairment [6, 13]. Therapeutic interventions targeting this interface, such as the sigma-2 receptor modulator CT1812 and the mGluR5 silent allosteric modulator BMS-984923 (ALX-001), aim to displace Aβo or block the downstream signaling of the complex to preserve synaptic function [4, 14]. These approaches represent a shift toward targeting the specific molecular mechanisms of Aβo-mediated toxicity rather than general amyloid clearance [7, 15].

Other names

Amyloid-beta oligomer-cellular prion protein interactionAβo-PrPC complexAmyloid-beta oligomer-PrPC-mGluR5 complexPrPC-Aβo hetero-assemblyAmyloid-beta oligomer receptor complex

Allosteric displacement of amyloid-beta oligomers from neuronal receptors and inhibition of the Aβo-PrPC-mGluR5 signaling pathway to prevent synaptic dysfunction.