MALAD

Because the pathogenesis of AD is complicated and related to the abnormality and dysfunction of multisystems, there has been no ideal drug for preventing and treating AD till now. The goal of current treatments is to improve neuronal dysfunction and produce only symptomatic benefits and drugs that act on the acetylcholine (ACh)-mediated system have been favored. It seems however necessary today to complete this symptomatic approach with a more disease-modifying one. In order to reach such a goal, it appears necessary to target one or several molecular causes implied in the pathogenesis of the disease. The aim of this project is to conceive and synthesize chemical compounds with adequate physicochemical properties and suitable in vitro profile to exert multiple activities of interest in the pathogenesis of AD. We have chosen among these causes the formation of senile plaques by aggregation of beta-amyloïd protein (AB) as a fundamental activity. In a first part of the project we want to develop, in order to prevent AB aggregation, agents liable to promote the cleavage of the APP by a-secretase allowing then the release of soluble and not amyloidogenic sAPPa. This effect can be obtained with serotonin 5-HT4 receptor (5-HT4R) agonists which are able to increase in vitro the extracellular release of sAPPa? decrease AB secretion in primary neurons and restore in vivo memory deficit in rat. Our goal will be to add to this first activity another manner to impact the amyloid aggregation in inhibiting the peripheric anionic site (PAS) of acetylcholinesterase (AChE), for which it has been shown that it forms a stable complex with BA favouring its aggregation into senile plaques. In a second part our program will focus on the development of multipotent agents which could exert direct AB aggregation and tau hyperphosphorylation inhibitory activities, in order to develop unique chemical structures which could be active on the two main molecular causes of AD. We propose, on the basis of our experience to produce such original Multi-Target-Directed Ligands with optimized physicochemical properties.