Journal of Pharmacovigilance

Inhibition of APP gamma-secretase: A promising tool for improving brain development in Down syndrome and APP-linked brain disorders

9^th International Conference and Exhibition on Pharmacovigilance & Drug Safety

July 17-18, 2017 Munich, Germany

Fiorenza Stagni, Andrea Giacomini, Sandra Guidi, Marco Emili and Renata Bartesaghi

University of Bologna, Italy

Scientific Tracks Abstracts: J Pharmacovigil

Abstract:

Statement of the Problem: No therapies currently exist for intellectual disability in Down syndrome (DS), a genetic disorder caused by triplication of chromosome 21. Intellectual disability is attributable to a severe reduction of neurogenesis that can be traced back to prenatal life stages. Accumulating evidence suggests that the triplicated gene APP (amyloid precursor protein) may be a particularly crucial determinant of neurogenesis alterations, because the AICD fragment of APP inhibits the mitogenic SHH pathway by increasing the expression levels of PTCH1, the inhibitory receptor of the SHH pathway. Since AICD derives from the cleavage operated by APP gamma-secretase, it may be envisaged that inhibitors of gamma-secretase may reduce excessive AICD levels with consequent restoration of the SHH pathway and, thus, neurogenesis. Methodology & Theoretical Orientation: We used the Ts65Dn mouse model of DS in order to establish whether neonatal treatment with an inhibitor of gamma secretase (ELND006) reduces AICD levels and restores neurogenesis in the hippocampus, a region that largely develops postnatally in rodents and plays a crucial role in learning and memory. Findings: We found that inhibition of gamma-secretase normalized the levels of AICD and PTCH1. This effect was accompanied by full restoration of hippocampal neurogenesis and total granule cell number. Treatment additionally restored neurite and synapse development and hippocampal functional connectivity. Conclusion & Significance: Results show that the APP/AICD system may be a key target for the improvement of neurodevelopmental alterations in DS. The inhibitor of gamma secretase used in our study, however, was not free of side effects. A challenging issue is now the creation of new molecules that, while selectively inhibiting APP gamma-secretase, are truly devoid of side effects. This achievement may have an important translational impact for DS and other APP-linked brain disorders.

Biography :

Fiorenza Stagni is a Postdoctoral Fellow at the Department of Biomedical and Neuromotor Sciences of the University of Bologna (Italy). In 2014 she obtained her PhD in Biomedical Sciences. In the framework of her doctoral work, she examined the effects of perinatal therapies on the neurodevelopmental alterations that characterize Down syndrome (DS), exploiting a mouse model of this pathology. She is currently involved in an international project aimed at identifying a panel of drugs that may be safely used during pregnancy or in infants in order to counteract the neurodevelopmental defects linked to DS. In 2016 she was awarded by the Trisomy 21 Research Society for the best dissertation in the field of DS (defended in 2014-2015). During the last years, she has received several Travel Awards for her the participation to international congresses and she was author of 13 publication in the field of preclinical studies for DS.

Email: fiorenza.stagni2@unibo.it