Ricerc@Sapienza

Down syndrome (DS) individuals around the age of 40 are more likely to develop Alzheimer¿s disease (AD) than the general population. The precise mechanisms by which trisomy 21 leads to the development of AD-like dementia in DS subjects have not been fully elucidated yet. In AD human brain has been observed an impairment of insulin signaling and increasing evidence supports the involvement of microRNAs (miRNAs) in the neurodegenerative process including AD and DS. In a recent study has been reported that miR-802 (a miRNA encoded on Chr 21) is involved in the onset of insulin resistance in obesity and in T2DM (type 2 diabetes mellitus) mouse models. In this study, we will investigate the role of miR-802 on insulin pathway in human DS brain prior and after AD development and in a mouse model of DS (Ts65Dn) as well. The use of different bioinformatics tools allowed us to identify PTEN and GSK3B as putative miR-802 targets involved in the insulin signaling. We suppose that miR-802 overexpression may occur in DS brain and blocking PTEN and GSK3B translation it may promote an impairment of insulin signaling responsible for the AD cognitive decline in DS adults. To test our hypothesis, we will evaluate the cognitive performance and age-associated changes for miR-802, PTEN and GSK3B as well as the activation state of insulin signaling in the hippocampus and cortex of Ts65Dn and wild type (WT) mice. In addition, we will perform ad hoc in vitro experiments on WT primary neurons to characterize and clarify how the miR-802 overexpression could contribute to develop insulin resistance. To confirm the results obtained in Ts65Dn mice we will evaluate the levels for miR-802, PTEN and GSK3B in human frontal cortex and in hippocampus of DS and DSAD patients. These results will be correlated with the activation state of insulin signaling in order to establish any possible direct or indirect relationships with miR-802 dysregulation and cognitive decline.