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

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Alzheimer Disease*/metabolism ; Alzheimer Disease*/genetics ; Acyltransferases*/metabolism ; Acyltransferases*/genetics ; Lipoylation* ; Hippocampus*/metabolism ; Disease Models, Animal* ; Mice, Transgenic*; Animals ; Humans ; Mice ; Male ; Female ; Neuronal Plasticity ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/prevention & control ; Palmitates/metabolism ; Amyloid beta-Peptides/metabolism ; Protein Processing, Post-Translational ; Acetyltransferases
    • Abstract:
      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-β (Aβ) metabolism. Here, 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. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Aβ deposition in the hippocampus and extended the lifespan of both male and female 3×Tg-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×Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with Aβ 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.
      Competing Interests: Competing interests statement:The authors declare no competing interest.
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    • Grant Information:
      Ricerca Corrente 2024 Fondazione Policlinico Universitario A. Gemelli IRCCS Ministero della Salute (Italy Ministry of Health); PRIN 2022-2022KP5LKS Ministero dell'Università e della Ricerca (MUR); Cariplo Telethon Joint Call - GJC21136 Fondazione Cariplo (Cariplo Foundation)
    • Contributed Indexing:
      Keywords: Alzheimer’s disease; BACE1; brain insulin resistance; protein S-palmitoylation; zDHHC
    • Accession Number:
      EC 2.3.- (Acyltransferases)
      18263-25-7 (2-bromopalmitate)
      EC 2.3.1.- (ZDHHC7 protein, human)
      0 (Palmitates)
      0 (Amyloid beta-Peptides)
      EC 2.3.1.- (Acetyltransferases)
    • Publication Date:
      Date Created: 20241126 Date Completed: 20241126 Latest Revision: 20241211
    • Publication Date:
      20241211
    • Accession Number:
      PMC11626176
    • Accession Number:
      10.1073/pnas.2402604121
    • Accession Number:
      39589870