Fiorenza Stagni
University of Bologna, Italy
Title: Inhibition of APP gamma-secretase: A promising tool for improving brain development in Down syndrome and APP-linked brain disorders
Biography
Biography: Fiorenza Stagni
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.