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SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy

Abstract

Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer’s Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.

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Fig. 1: SIRT1 enhances OGA expression and modulates tau O-GlcNAcylation.
Fig. 2: SIRT1 increases luciferase activity driven by OGA promoter via transcriptional factor C/EBPα.
Fig. 3: SIRT1 interacts with and deacetylates C/EBPα at K92.
Fig. 4: SIRT1 deletion exacerbates phosphorylation of tau and alters synaptosomal location of tau.
Fig. 5: Synaptic dysfunction and cognitive impairment occur in SIRT1 flox/Cre+mice.
Fig. 6: Proposed mechanism by which SIRT1 deletion leads to synaptic dysfunction and cognitive deficits.

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Funding

This work was supported in part by Nantong University and grants from National Natural Science Foundation of China (81872875, 81170317 and 81473218 to WQ; 81503077 to XMY; 82101608 to YYL), the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD).

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WQ, FL and XCW conceived and designed the study. XMY, YYL, XF and FH performed the experiments. YYQ, QG, CHZ, ZZ, LYX and JZB performed biochemical analysis. WQ wrote the manuscript. XMY, YYL, XF edited the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Xiaochuan Wang, Fei Liu or Wei Qian.

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Yin, X., Li, Y., Fan, X. et al. SIRT1 deficiency increases O-GlcNAcylation of tau, mediating synaptic tauopathy. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01689-2

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