SIRT1 deacetylates tau and reduces pathogenic tau spread in a mouse model of tauopathy

Sang Won Min, Peter Dongmin Sohn, Yaqiao Li, Nino Devidze, Jeffrey R. Johnson, Nevan J. Krogan, Eliezer Masliah, Sue Ann Mok, Jason E. Gestwicki, Li Gan

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The nicotinamide adenosine dinucleotide-dependent class-III protein deacetylase SIRT1 is one of the major enzymes involved in removal of acetyl groups from tau in vitro. However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion. We show that SIRT1 deficiency leads to exacerbation of premature mortality, synapse loss, and behavioral disinhibition in tauP301S transgenic mice of both sexes. By contrast, SIRT1 overexpression by stereotaxic delivery of adeno-associated virus that encodes SIRT1 into the hippocampus reduces acetylated K174 tau. Furthermore, SIRT1 overexpression significantly attenuates the spread of tau pathology into anatomically connected brain regions of tauP301S transgenic mice of both sexes. These findings suggest the functional importance of SIRT1 in regulating pathogenic tau acetylation and in suppressing the spread of tau pathology in vivo.

Original languageEnglish
Pages (from-to)3680-3688
Number of pages9
JournalJournal of Neuroscience
Volume38
Issue number15
DOIs
StatePublished - 11 Apr 2018
Externally publishedYes

Keywords

  • Acetylation
  • Dementia
  • SIRT1
  • Tau
  • Tau spread

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