Prion Protein Antagonists Rescue Alzheimer's Amyloid-β-Related Cognitive Deficits

Abstract

Recent studies revealed that cellular prion protein on neurons bind Alzheimer's amyloid-β oligomers, causing neurotoxic effects. A new article in Cell Reports by Gunther and colleagues (Cell Rep. 2019; 26:145-158) shows that an orally administered cellular prion protein antagonist can rescue synaptic and cognitive deficits in Alzheimer's mice overexpressing amyloid-β.

Keywords: Alzheimer’s disease; amyloid-β oligomers; antagonist; cellular prion protein; cognition.

Figure 1.. PrP^C antagonists improve synaptic function and spatial memory in a mouse model of Alzheimer’s disease.

Binding of amyloid-β oligomers (Aβo, black circles) to neuronal cellular prion protein (PrP^C) leads to synaptic dysfunction and memory impairments. Centrally administered compound Z (red circles) and orally delivered Poly (4-styrenesulfonic acid-co-maleic acid) (PSCMA) that crosses the blood-brain barrier (BBB) (gray circles), both inhibit Aβo binding to PrP^C on neurons (blue). This improves synaptic function and spatial memory deficit in Alzheimer’s mouse model of β-amyloidosis. Endothelial cells (red), astrocytes (purple) and oligodendrocytes (green) also express PrP^C. Whether inhibiting PrP^C-Aβo interactions on non-neuronal cell types can affect their function and/or contribute to the observed beneficial effects of compound Z or PSCMA, remains presently unclear. For example, whether compound Z or PSCMA can impact low-density lipoprotein receptor-related protein-1 (LRP1)-mediated clearance of PrP^C-bound Aβ across the blood-brain barrier (BBB) is currently unknown. Do compound Z and PSCMA interact and alter functions of soluble PrP^C interaction with Aβo which can affect fibril formation (gray box) remains elusive.