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U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>Protein post-translational modifications (PTM) 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 PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-\u03b2 (A\u03b2) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3\u00d7Tg-AD mice and post-mortem Alzheimer\u2019s disease (AD) patients. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the A\u03b2 deposition in the hippocampus and extended the lifespan of both male and female 3\u00d7Tg-AD mice. Moreover, hippocampal silencing of zDHHC7 prevented the onset of cognitive deficits in the same experimental model. We also identified a FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression, which was triggered by brain insulin resistance in 3\u00d7Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with A\u03b2 1 to 42 load and they inversely correlated with Mini Mental State Examination scores. Our data reveal a key role of both zDHHC7 overexpression and protein hyperpalmitoylation in the onset and progression of AD-related alterations of synaptic plasticity and memory.<\/jats:p>","DOI":"10.1073\/pnas.2402604121","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T12:21:54Z","timestamp":1732623714000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"121","author":[{"given":"Francesca","family":"Natale","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Rome 00168, Italy"},{"name":"Fondazione Policlinico Universitario A. 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