Inhibition of zDHHC7-driven protein S- palmitoylation prevents cognitive deficits in an experimental model of Alzheimer's disease

• 成果类型: Article
• 署名作者: Natale, Francesca; Spinelli, Matteo; Rinaudo, Marco; Gulisano, Walter; Sarrapochiello, Ida Nifo; Aceto, Giuseppe; Puzzo, Daniela; Fusco, Salvatore; Grassi, Claudio
• 署名单位: Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; University of Catania; IRCCS - Oasi Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13885
• DOI: 10.1073/pnas.2402604121
• 发表日期: 2024-12-03
• 关键词: brain insulin-resistance; amyloid deposition; 2-bromopalmitate; plasticity; bace1

摘要

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-f3 (Af3) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S- palmitoylation in hippocampi of both 3xTg- AD mice and post- mortem Alzheimer's disease (AD) patients. Chronic intranasal administration of the S- palmitoylation inhibitor 2- bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Af3 deposition in the hippocampus and extended the lifespan of both male and female 3xTg- 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 3xTg- AD mice. Finally, in hippocampi of AD patients S- palmitoylation levels of Beta- Secretase 1 were associated with Af3 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.