Soluble Aβ aggregates can inhibit prion propagation

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 β-protein (Aβ) can tightly bind to PrPC, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrPC and emphasize the bidirectional nature of the interplay between Aβ and PrPC in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common

Pharmacological chaperone for the structured domain of human prion protein.

In prion diseases, the misfolded protein aggregates are derived from cellular prion protein (PrP(C)). Numerous ligands have been reported to bind to human PrP(C) (huPrP), but none to the structured region with the affinity required for a pharmacological chaperone. Using equilibrium dialysis, we screened molecules previously suggested to interact with PrP to discriminate between those which did not interact with PrP, behaved as nonspecific polyionic aggregates or formed a genuine interaction. Those that bind could potentially act as pharmacological chaperones. Here we report that a cationic tetrapyrrole [Fe(III)-TMPyP], which displays potent antiprion activity, binds to the structured region of huPrP. Using a battery of biophysical techniques, we demonstrate that Fe(III)-TMPyP forms a 1∶1 complex via the structured C terminus of huPrP with a K(d) of 4.5 ± 2 μM, which is in the range of its IC(50) for curing prion-infected cells of 1.6 ± 0.4 μM and the concentration required to inhibit protein-misfolding cyclic amplification. Therefore, this molecule tests the hypothesis that stabilization of huPrP(C), as a principle, could be used in the treatment of human prion disease. The identification of a binding site with a defined 3D structure opens up the possibility of designing small molecules that stabilize huPrP and prevent its conversion into the disease-associated form

Putative Mechanism for ADDL inhibition of RML propagation. from Soluble Aβ aggregates can inhibit prion propagation

Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the cells innate clearance systems and dilutional effect of cell division, thus the cells remain chronically infected. However when ADDLs are added they bind to PrPC at the cell surface preventing conversion to PrPSc. This reduction in the conversion rate allows the PrPSc to be cleared over time, resulting in reduction in PrPSc levels and cell curing

Author Correction: EMPReSS: standardized phenotype screens for functional annotation of the mouse genome

International audienceCorrection to: Nature Genetics, published online 1 November 2005.In the version of this article initially published, members of the Eumorphia Consortium appeared in the Supplementary Information but were not included in the main article. The full list of members appears below