Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. Interestingly, DS patients have an increased risk for cognitive decline and Alzheimer disease (AD). Several studies reveal that DS and AD neuropathology have many common features including deposition of senile plaques and neurofibrillary tangles, and cellular dysfunction such as increased oxidative stress and the impairment of protein homeostasis. A growing number of studies suggests that dysfunction of the unfolded protein response (UPR) plays a pivotal role in cellular dysfunction and death in AD. Recent data from our laboratory demonstrated the potential contribution of the UPR and more specifically the role of PERK-mediated disruption of protein synthesis in DS mouse models at different ages. Therefore, our project aim to investigate if restoring PERK pathway, by using a well-established PERK inhibitor (GSK2606414), could mitigate the early UPR activation and result in reduced brain pathology and improved cognition in a DS mouse model. We will use Ts2Cje mice that carry the trisomy of the Chr16 (homologous to human Chr21). The PERK inhibitor will be delivered by intranasal route to target directly the brain and the treatment of Ts2Cje will start at 1 month of age before the appearance of UPR stress, neuropathological hallmarks and cognitive decline. Pilot studies would be needed before the treatment to select the dose of the compound. For the treatment mice will be divided in two groups: Mice from group 1 will be treated for 2 months and sacrificed to test inhibition of PERK by immunochemical and immunofluorescence analysis. Mice from group 2 will be treated for 5 months, tested for cognitive performances and sacrificed to analyse AD-related pathology. Results obtained from this study aim to propose novel therapeutic strategies able to recover UPR alteration and reduce cognitive decline in DS individuals.
