RESUMEN
Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrPC). Ligands that bind to PrPC can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid ß-protein (Aß) can tightly bind to PrPC, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aß assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aß preparations, we found that the form of Aß assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aß which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aß can compete with prions for binding to PrPC and emphasize the bidirectional nature of the interplay between Aß and PrPC in Alzheimer's and prion diseases. Such inhibitory effects of Aß on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aß deposition is common.
