Protein 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.
9 Maggio 2025