In the last decade, our laboratory focused the attention on the analysis of oxidative modifications of proteins and how dysfunction of selected proteins translate into pathological features of a disease state. By following this approach we contributed to shed light on critical molecular determinants underlying aging and cognitive dysfunction. Particularly, my team focuses on redox mechanisms of neurodegeneration in Down Syndrome (DS) and Alzheimer Disease (AD). Results obtained by the analysis of human specimens and studies from mouse and cellular models of the disease reveal a molecular link between protein oxidation/aggregation, the integrity of the protein quality control system (proteasome, UPS and autophagy), dysfunction of energy metabolism and neurodegeneration. Many common pathological hallmarks exist between DS and AD, including deposition of amyloid plaques, NFTs, increased oxidative damage and impaired mitochondrial function, among others. Intriguingly, we propose that all of these processes seem to be joined by a ‘leitmotif’ – oxidative stress – since they are all the cause and/or the consequence of increased free-radical burden. In addition, other than proteostasis and glucose metabolism, redox proteomics studies allowed the identification of oxidized proteins belonging to several dysfunctional pathways among which, detoxification systems, excitotoxicity or synapse function that highly correlates with DS and AD pathological features supporting the role of protein oxidative damage in neurondegeneration and cognitive decline.
Further, we recently demonstrated the disturbance of PI3K/Akt/mTOR axis in DS brain, prior and after development of AD. Aberrant mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function and autophagy. All these events are key players in age-related cognitive decline and contribute to the development of Alzheimer-like dementia in DS.
Further, we are currently investigating the role of insulin resistance in the onset of neurodegeneration and the efficacy of drugs to restore physiological insulin signalling.
PUBMED
