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.
During the last decade the scientific community has devoted great attention to age-related cognitive decline and the number of these studies will most likely increase in the near future. Cognitive declines, including AD-like dementia in DS population, have a big impact on both cost of healthcare and the quality of life. Although notable strides have been made with regard to therapeutic strategies aimed slow or halt neurodegeneration, pharmacological treatment to date have generally produced minimal or disappointing results. Recently, the evidence of a strong contribute of protein dys-homeostasis has emerged in the development of neurodegenerative diseases. Furthermore, despite the epidemiological evidence of a tight correlation between neurodegenerative and metabolic diseases, the molecular mechanisms linking metabolic dyshomeostasis and cognitive impairment are still poorly understood. The novel idea underlying this project is that the early chronic UPR activation, which represents a key molecular alteration leading to age- related cognitive decline in DS is associated with the development and progression of brain insulin resistance (BIR). . Brain dysmetabolism as well as Increased ER stress are considered strong risk factors for cognitive deterioration however no data concerning their combined effect been produced yet. Therfore, UPR/BIR may represent a novel target to slow or delay the DS- and age- related cognitive decline. In addition, the UPR/BIR crosstalk during AD-like neurodegeneration is a new concept and deepening the knowledge of UPR and BIR relationship in DS samples will allow to understand the molecular mechanism that links aberrant proteostasis and metabolic defects posing the basis for therapeutic interventions targeting one or the other or both the components. The use of Blood-derived cells from young DS living patients represents a further innovation of this project. Indeed, this is a unique model to study early alterations, driven by trisomic condition, in peripheral samples from living subjects. Furthermore, it allows to understands the mechanism leading to cell degeneration shared with neuronal cells. Thanks to our collaboration with Dr. Diletta Valentini, pediatrician at Bambino Gesù pediatric hospital (OPBG) in Rome, we have the access to a large number of blood samples from DS children that could allow us to expand the analysis of the molecular mechanisms involved in the alterations observed in DS phenotype. Epstein Barr virus (EBV) immortalized B-cells cells will be obtained from a cohort of subjects that account for about 600 young DS patients and age-matched healthy individuals routinely screened every year. We plan to analyze blood from selected DS and age-matched healthy individuals (6 each group) that will be processed for the isolation of B-cells and immortalization by Epstein Barr virus (EBV) in collaboration with Dr. Valentina Folgiero from OPBG. These stable cell lines will allow to perform experiments within the same population thus corroborating the consistency and reproducibility of the data. Preliminary data on both primary PBMCs and EBV B-cell confirm shared pathological alterations between blood-derived DS cell and frontal cortex from DS human patients. Early preliminary findings strongly encourage to perform the present project, since the results generated by the investigators, each focusing on targets different but all equally crucial and strictly converging, may offer significant advances in the understanding pathophysiological mechanisms involved in DS- and age- associated cognitive decline. The impact of the proposed work is therefore substantial, in the light of both the impact of diet on incidence of diseases and the increasing number of people expected to be affected by dementia worldwide in the near future. The characterization of the exact pathogenic pathways involved in the development of these conditions might help to understand how specific nutrients and dietary patterns impact on functional decline of specific organs.
The results obtained may suggest novel and promising therapy and it could pave the way to develop relatively simple nutritional strategies to counteract or delay the onset of metabolic and functional alterations characteristic of ageing that hopefully could have the potential not just to alleviate the symptoms but also to modify the course of the declined cognition in DS subjects.