The pathogenesis of soluble PrP fragments containing Aβ binding sites.

Prion protein (PrP) has proven to bind amyloid beta (Aβ) oligomers with high affinity, changing our understanding of both prion diseases (PD) and Alzheimer's disease (AD) at the molecular and phenotypic levels, although the latter currently lacks sufficient attentions. Transgenic mice expressing anchorless PrP developed unusual diseases reminiscent of AD with tremendous amyloid plaque formation. In this review, we described two interesting observations at the phenotypic level. First, common pathogenic mutations of the PRNP gene in Gerstmann-Sträussler-Scheinker (GSS) syndrome were clustered at PrP95-105. Meanwhile, all nonsense PRNP mutations that generated soluble PrP 95-105 exhibited phenotypes with abundant amyloid formations. We speculate that PrP-Aβ oligomers binding might be the underlying mechanism of the predominant amyloid phenotypes. Second, soluble PrP-Aβ oligomer complexes might exist in the extracellular space at the beginning of both PD and AD and subserve an initial neuroprotective function. Thus, the diseases would only present after long-term accumulation. This might be the central common pathogenic event of both PD and AD.