Preventive therapy of mental retardation in down syndrome by a novel gamma-secretase inhibitor: focus on app-dependent mechanisms in neurodevelopment.

Coordinated by Renata Bartesaghi from Biomedical and Neuromotor Sciences Department – DIBINEM with Laura Calzà from Pharmacy and Biotechnology Department – FaBiT. Also the University of Pavia is partner of this research.

Summary

Down syndrome (DS) is a genetic pathology caused by triplication of human chromosome 21. Individuals with DS may have various medical problems, but intellectual disability is the unavoidable hallmark and the most invalidating aspect of this pathology. In spite of numerous efforts, the mechanisms whereby gene triplication leads to the DS phenotype have not been elucidated and there are no therapies to rescue brain developmental alterations and mental disability. Generalised neurogenesis impairment during critical developmental stages and altered dendritic maturation appear to be major determinants of the reduced brain size and, hence, of mental retardation in individuals with DS. Recent data suggest that the trisomic gene APP (amyloid precursor protein), a gene important for neuron generation and differentiation, may be a key candidate for both these neurodevelopmental alterations in DS. This hypothesis derives from preliminary data in vitro showing that increased levels of AICD, a cleavage products of APP by γ-secretase, impair proliferation of trisomic neural precursor cells and dendritic development. Since increased AICD levels in the DS brain are inevitable due to APP triplication, a rational therapeutic approach would be to prevent AICD formation by inhibiting the activity of APP γ-secretase. The overall goal of this project is to establish whether it is possible to pharmacologically cure impairment of brain development in DS by using a selective APP γ-secretase inhibitor, in order to reduce AICD formation and restore neurogenesis and neuron maturation. We will use the Ts65Dn mouse model because it recapitulates numerous abnormalities of the DS brain. If, as we expect, this therapeutic approach will restore trisomy-linked brain alterations, results might open the way to clinical trials aimed at curing intellectual disability in children with DS.