Down syndrome (DS) is one of the most common causes of intellectual disability characterized by the development of Alzheimer Disease (AD). Chronic oxidative stress and increased ER stress are key factors that contribute to the development of AD. Markers specific for UPR activation, such as PERK-P are increased in AD, while the reduction of PERK activity in AD mice is able to rescues memory deficits. Recent studies from our laboratory observed the early activation of the PERK arm in DS mice. Under ER stress, PERK activation lead, on one hand to the reduction of protein translation, through Eif2a and on the other hand to the induction of antioxidant response through NRF2 nuclear translocation. In turn, NRF2 signal activation plays a significant role in the reduction of ER stress. The induction of the antioxidant response depends on the competition on ARE sequences between NRF2 and the transcription repressor BACH1 (encoded on Chr 21) . The analysis of NRF2 levels demonstrate a decrease in AD and AD-like dementia suggesting its uncoupling from PERK signaling during pathological UPR induction. In agreement, BACH1 expression increases during aging, AD and DS pathology. Preliminary data from our laboratory suggest, for the first time, a link between aberrant PERK activation, NRF2 depletion and BACH1 overexpression in brain and PBMC from DS subjects. However, the molecular mechanisms involved are still undetermined. The overall objective of the project is to understand the processes that lead to PERK/NRF2 uncoupling in DS with the idea of identifying compounds able to rescue their physiological interaction and reduce brain damage. The central hypothesis is that trisomy 21 lead to chronic PERK overactivation contributing, with BACH1 overexpression, to NRF2 depletion. The reduction of PERK chronic overactivation could allow to the rescue of PERK/NRF2 axis thus re-establishing proper proteostasis and reducing oxidative damage.
