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Prion diseases are fatal neurodegenerative disorders affecting humans and animals. A critical event in prion diseases is the accumulation in the central nervous system of the abnormally folded PrPSc protein that is the proteaseresistant isoform of a normal cellular protein encoded by the host and called PrPC. According to the “protein only” hypothesis proposed by Prusiner [1], prion agents are mostly composed of the pathological PrPSc. During prion replication, PrPSc can trigger the autocatalytic conversion of PrPC into PrPSc and catalyze its conversion into a misfolded form that becomes pathological. The conversion process involves several PrPSc intermediates (dimers, trimers, small soluble oligomers and bigger aggregates) that auto-assemble into proto fibrils, which in turns grow into amyloid fibrils [2]. Large fibrils can break into small fragments (called seeds) that will serve to propagate de novo the prion agents [3]. Due to the unique nature of prion agents and their mode of propagation, both PrPC and PrPSc have been considered as main targets in the development of diagnostic and therapeutic approaches. The majority of screening assays performed in prion-infected cells to identify new anti-prion drugs have focused on reducing the level of PrPSc. However, most of the time, it is difficult to assess which PrPSc species are targeted by the drug. Indeed, after proteinase K (PK) treatment and in SDS and reducing conditions, all PrPSc species are completely dissociated, leading to a monomeric band that corresponds to the PrP(27-30) marker. Thus, reduction of the PrP(27-30) marker reflects a global decrease of PrPSc levels in the cells that is not always correlated with diminished infectivity. Evidences showed that fibrils serve as “reservoirs” to trap small neurotoxic species [4], thus it might be better to fix their amyloid structure rather than to break them. Caution has to be applied when using anti-PrP compounds because the solubilization of large aggregates could indirectly produce seeds that “boost” the prion replication process [3]. A strategy that has not been explored until now, was to search for small molecules that interact with PrPSc and favor the formation of multimers/oligomers of PrP(27-30) through a cross-linking process [5] (Figure 1). Although it seems totally contradictory to promote the formation of PrPSc oligomeric species, supposed to be the most infectious species, we hypothesized that small chemical molecules could block small or large PrPSc species in a pathway that is not competent for prion replication. In a first study, we identified a family of thienyl pyrimidine compounds that favor resistant-SDS PrPSc (rSDS-PrPSc) oligomers and diminish prion infectivity both in cell lysates and brain homogenates [5]. Thereafter, studies on Alzheimer’s disease showed that small molecules can be powerful tools for the modulation of amyloid formation cascades and demonstrated that acceleration of fibril formation reduces Aβ42 toxicity in human neuroblastoma cells and in rat brain slices [6]. Interestingly, oligomer modulators tend to demonstrate that small molecules can

Trapping the oligomers: new promises in neurosciences