Beta-amyloid oligomers and cellular prion protein in Alzheimer's disease

Abstract

Prefibrillar oligomers of the beta-amyloid peptide (A beta) are recognized as potential mediators of Alzheimer's disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric A beta assemblies rather than to A beta monomers or to amyloid plaques. However, the molecular sites of A beta oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP(C)) has been shown to act as a functional receptor for A beta oligomers in brain slices. Because PrP(C) serves as the substrate for Creutzfeldt-Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of A beta oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP(C) as a receptor for A beta oligomers.

Fig. 1

Aβ plaque deposition in transgenic mouse brain. Cerebral cortex sections of 12 month old APPswe/PSen1ΔE9 transgenic mice [83] (Jackson Laboratories) were stained for Aβ (green; anti-Aβ polyclonal antibody, Cell Signaling Technologies, Inc., number 2545), nissl (red), and nuclei (blue, DAPI). Note the amyloid plaques (arrows). Scale bar is 100 μm

Fig. 2

Model of Aβ₄₂ action through PrP^C receptor. APP processing yields Aβ monomers, which undergo oligomerization eventually forming amyloid plaques. Aβ oligomers bind to PrP^C, inducing LTP inhibition [84]. We hypothesize that the same mechanism may lead to dendritic spine retraction via synaptotoxic action, with subsequent neuritic dystrophy and neurodegenerative pathology. These later steps are coupled to tauopathy and memory impairment in humans. The oligomeric infectious form of PrP and PrP^Sc independently induces neurodegeneration in a PrP^C-dependent fashion. See text for discussion