rotein post-translational modifications play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a post-translational modification catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. We demonstrated that high fat diet (HFD)-induced brain insulin resistance caused LTP and memory impairment due to the accumulation of palmitic acid and increased expression/activation of zDHHC3 leading to hyper-palmitoylation of GluA1 in the hippocampus of mice. Palmitoyl-proteome analysis revealed changes of S-palmitoylated protein pattern in HFD hippocampi. Moreover, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer’s disease (AD) patients. Finally, both intranasal administration of the palmitoylation inhibitor 2- bromopalmitate and hippocampus-specific knockdown of zDHHC expression abolished the HFD- or ADrelated molecular and behavioral changes of brain plasticity and cognition. Our data indicate that aberrant protein S-palmitoylation plays a critical role in hippocampal synaptic plasticity and memory deficits observed in experimental models of metabolic and neurodegenerative disease and suggest zDHHCs as new target for therapeutic interventions against cognitive decline.
09/05/2025 ore 12.00 aula Ulrico Bracci (Policlinico Umberto I) Prof. Salvatore Fusco-Università Cattolica, Roma.