Down syndrome (DS) is the main genetic cause of intellectual disability. Decreased proliferation of Neural Progenitor Cells (NPC), widespread neurogenesis impairment and increased astrogliogenesis are considered among the major determinants of brain atrophy and intellectual disability in DS individuals. The best characterized and studied animal model for DS is the Ts65Dn mouse line which recapitulates several features of the human pathology, including cognitive impairment. In the recent years studies suggested that perinatal pharmacotherapies targeting NPC alterations may represent potential interventions in DS. However, at present, no pharmacotherapies are suitable for clinical application.
Thus, the need to identify new and safe pharmacotherapies to improve intellectual disability in DS patients. Based on these data, our overall goal was to unravel novel mechanisms underlying We generated and phenotypically characterized NPC from Ts65Dn and euploid pups (P1, 2). We then targeted NPC alterations using at first a phenotypic-based approach that identified 30
FDA/EMA approved drugs able to correct trisomic NPC defective proliferation. Importantly, among the potential hits we identified the immunosuppressant cyclosporine A (CSA). We showed that a neonatal treatment with CSA (P3-P15) corrected the whole triad of defects of DS brain. In parallel, we used a target based approach, exploiting the effect of an agonist of the tropomyosin
receptor kinase B, 7,8-DHF, and corn oil on neurogenesis in vitro and in vivo, also evaluating the cognitive performances.
In the last part of this thesis we identified new molecular mechanisms altered in trisomic NPC in response to the key astrocytic signal thrombospondin-1. Taken together these data showed that trisomic NPC dysfunctions are pharmacologically relevant
targets in DS
