My research is currently focused on understanding the role of defective proteostasis in the development of Alzheimer’s-like dementia in order to propose novel effective therapeutic approaches that might ameliorate cognitive decline. Starting in 2005, I dedicated my research on the studies of oxidative stress role in the development of neurodegenerative disease. Thanks to my experience at University of Kentucky in the laboratory of prof. D. Allan Butterfield I have been involved in the setting of proteomics approaches comprising redox proteomics. Through these use of techniques, my following research projects contributed to highlight the role of increased oxidative stress and dysfunctional protein degradation systems in the pathogenesis and progression of Alzheimer Disease-like dementia. Indeed, we demonstrated that the oxidative modification (carbonylation, protein bound HNE and nitration) of proteins, belonging to different degradation systems (proteasome and autophagy) impairs their functionality and contributes to the progression of the neurodegenerative process. Therefore, collected data postulated that aberrant proteostasis, observed in both Alzheimer’s and Down syndrome patients, is strictly associated with the increase of oxidative damage as result of compromised antioxidant response and faulty protein degradative systems. Recent studies revealed that chronic induction of the unfolded protein response has a prominent role in the development of AD- like dementia in DS brain. Indeed, the pharmacological rescue of UPR function leads to the reduction in neuropathological hallmarks and to decrease in protein oxidation in a mechanism involving the Nrf2 antioxidant response. The results obtained led to the publication of several articles on peer-reviewed journals and based on these we started to test a number of compounds for the treatment and prevention of cognitive decline in Down syndrome mice.