Drug Discovery for Alzheimer’s Disease: Screen of small molecules able to inhibit PrPC-Abos interaction using ICC and the role of Cu2+ in this scenarios.

The initial report that cellular prion protein (PrPC) mediates toxicity of amyloid-b species linked to Alzheimer’s Disease (AD) was initially treated with scepticism, but growing evidence supports the claim that there is a high-affinity interaction and its molecular basis is being unravelled, while recent studies have identified possible downstream toxic mechanisms. Determination of the clinical significance of such interactions between PrPC and Ab species will be therapeutically useful. PrPC plays also a protective role in response to oxidative stress induced by Cu2+, but the mechanism is still unclear. Recently, it has been shown that NMDARs activity is modulated by PrPC in a copper-dependent manner. The purpouse of this work was to perform an HTS on different libraries of small compounds with affinity for PrPC, Abos chelators and BACE inhibitors, in order to establish and verify their in vitro ability to disrupt Aβos-PrPC interaction, to investigate their structureactivity relationship and identify a lead compound. Furthermore, Cu2+ effect on PrPC was investigated in N2a cells in presence of Ab1-42.