Ricerc@Sapienza

Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis (proteostasis) is essential for normal brain function and the unfolded protein response (UPR) holds a key role in its preservation. However, little is known about the mechanisms inducing disturbed proteostasis and their involvement in DS pathology. We recently reported that the dysregulation of the PERK branch of the UPR leads to aberrant proteostasis and cell death contributing to the progression of Alzheimer Disease (AD)-like dementia in DS brain. In parallel, studies from our laboratory demonstrated that brain insulin resistance (BIR) develops early in DS and is associated with cognitive decline. Intriguingly, an extensive crosstalk between UPR and BIR has been documented, however the molecular mechanisms involved, as well as, and the UPR/BIR mutual role in promoting neurodegeneration, are mostly unknown. This proposal aims to investigate the role of UPR/BIR interaction in DS with the final intent of proposing novel therapeutic strategies able to improve proteostasis, reduce metabolic defects and impede the development of AD-like dementia. To identify the detrimental link between UPR and BIR, we will take advantage of lymphoblastoid cells from DS living subjects stimulated with a cocktail of insulin and palmitic acid, and subsequently treated by pharmacological stimuli. Further, to investigate the mutual relationship between UPR and BIR in the progression of brain pathology and cognitive decline, we will use a mouse model of DS fed for 6 weeks with high-fat diet (HFD) compared to the euploid strain. By pharmacologically targeting specific components of the UPR in HFD-treated DS mice, we aim to rescue ER stress, mitigate experimentally induced metabolic alterations and improve cognitive performances. Results from the present project might support the UPR/BIR crosstalk as a valuable therapeutic target to reduce AD development in DS but also in normal population.