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

Yin, Xiaomin; Li, Yuanyuan; Fan, Xing; Huang, Fang; Qiu, Yanyan; Zhao, Chenhao; Zhou, Zheng; Gu, Qun; Xia, Liye; Bao, Junze; Wang, Xiaochuan; Liu, Fei; Qian, Wei

doi:10.1038/s41380-022-01689-2

Cited by 14 publications

(5 citation statements)

References 90 publications

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“…To the best of our knowledge, we did not find any direct or indirect correlation among these bacteria ( Candidatus_Saccharimonas, Candidatus_Actinomarina, Mucispirillum , and Helicobacter ) and OGA/OGT and O-GlcNAc. But we found a couple of flora that were associated with SCFAs ( Wang et al, 2020 ; Gu et al, 2021 ; Liu Q. et al, 2021 ; Luo L. et al, 2022 ), glucose metabolism ( Gao et al, 2020 ; Li L. et al, 2022 ; Luo L. et al, 2022 ; Ma Q. et al, 2022 ), glycolysis ( Feichtinger et al, 2017 ; Zhou et al, 2021 ; Li L. et al, 2022 ), bile acids ( Alizadeh and Raufman, 2022 ; Jian et al, 2022 ; Yin et al, 2022 ; Yuan et al, 2022 ) and other aspects. The intracerebral glucose metabolism and glycolysis, which produced the major donor substrate for O-GlcNAcylation ( Liu X. et al, 2021 ), were regulated directly by intestinal microbiota and their metabolites.…”

Section: Discussionmentioning

confidence: 87%

“…The O-GlcNAcylation is regulated by the “writer” O-GlcNAc transferase (OGT) and the “eraser” O-GlcNAcase (OGA), which catalyze the addition and hydrolyzation of the GlcNAc moiety to the proteins, respectively ( Chatham et al, 2021 ). To date, this dynamic PTM has been shown to participate in the pathogenesis and pathological process of various stress-related diseases, ranging from tumors ( Hanover et al, 2018 ) to diabetes ( Hegyi et al, 2020 ) and neurodegeneration ( Yin et al, 2022 ). Hence, a developing hypothesis is that any abnormal physiological state with changed stress levels has an O-GlcNAc component ( Yang and Suh, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Liuwei Dihuang formula ameliorates chronic stress-induced emotional and cognitive impairments in mice by elevating hippocampal O-GlcNAc modification

Huang

Wang²,

Liu³

et al. 2023

Front. Neurosci.

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A substantial body of evidence has indicated that intracerebral O-linked N-acetyl-β-D-glucosamine (O-GlcNAc), a generalized post-translational modification, was emerging as an effective regulator of stress-induced emotional and cognitive impairments. Our previous studies showed that the Liuwei Dihuang formula (LW) significantly improved the emotional and cognitive dysfunctions in various types of stress mouse models. In the current study, we sought to determine the effects of LW on intracerebral O-GlcNAc levels in chronic unpredictable mild stress (CUMS) mice. The dynamic behavioral tests showed that anxiety- and depression-like behaviors and object recognition memory of CUMS mice were improved in a dose-dependent manner after LW treatment. Moreover, linear discriminate analysis (LEfSe) of genera abundance revealed a significant difference in microbiome among the study groups. LW showed a great impact on the relative abundance of these gut microbiota in CUMS mice and reinstated them to control mouse levels. We found that LW potentially altered the Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis process, and the abundance of O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in CUMS mice, which was inferred using PICRUSt analysis. We further verified advantageous changes in hippocampal O-GlcNAc modification of CUMS mice following LW administration, as well as changes in the levels of OGA and OGT. In summary, LW intervention increased the levels of hippocampal O-GlcNAc modification and ameliorated the emotional and cognitive impairments induced by chronic stress in CUMS mice. LW therefore could be considered a potential prophylactic and therapeutic agent for chronic stress.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Liuwei Dihuang formula ameliorates chronic stress-induced emotional and cognitive impairments in mice by elevating hippocampal O-GlcNAc modification

Huang

Wang²,

Liu³

et al. 2023

Front. Neurosci.

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“…We did not perform further evaluation in this study. Therefore, if experimental conditions allow, it would be more ideal to establish a SIRT1 knockout senescence mouse model by gene knockout [25] and to perform the necessary blood levels of SGLT2 inhibitors to further validate the effectiveness of our findings. In addition, other downstream signaling pathways activated by SIRT1 need to be further explored, and the effects of SGLT2 inhibitors on other types of aging phenotypes need to be further explored [26] [27].…”

Section: Discussionmentioning

confidence: 93%

Protective Effect of SGLT2 Inhibitor on D-Galactose-Induced Senescence in Mice and Its Mechanism

Ma¹,

Xu²,

Jin³

et al. 2023

JBM

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Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice were divided into control group (13) and model group ( 53), and the model group was moulded by subcutaneous injection of D-galactose into the back of the neck, while the control group was treated with equal amount of saline for 8 weeks. The weight of each group of mice was observed and recorded every 7 days, and two groups of mice were randomly selected for frozen sections of brain tissue at the end of the modelling period to verify the aging model. 2. After the aging model was successfully established, the aging groups were divided into 5 groups: model group, dagliflozin-treated group (high and low dose), and dagliflozin + ex527-inhibited group (high and low dose). Fasting blood glucose was measured in each group every 2 weeks for 8 weeks. At the end of treatment, Morris water maze was performed at the end of the treatment. After execution of the mice, the organ indices of heart, brain, liver, kidney and spleen were measured; the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined. Results: After the successful establishment of the aging model, it was found that during the treatment phase of dagliflozin. 1) The organ indices of mice in the aging group were significantly lower than those of other groups, and no significant hypoglycemia was observed throughout the treatment process. 2) In the water maze test, mice in the aging group had a significantly longer latency in the plateau phase compared to the control and treatment groups, while the number of times the mice crossed the original plateau and the percentage of time spent exploring the original plateau quadrant were reduced after the plateau was removed. 3

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“…They also found that the increased O-GlcNAcylation of tau is accompanied by the enhanced site-specific phosphorylation of tau in the SIRT1 flox/Cre+ brain. Also, the conditional deletion of SIRT1 in mice brains changes the synaptosomal proportion of site-specific phospho-tau and causes dendrites spine impairment and synaptic dysfunction [ 57 ].…”

Section: Post-translational Modificationmentioning

confidence: 99%

Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

Rawat

Sehar

Bisht

et al. 2022

IJMS

132

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Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer’s brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, Alzheimer’s disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington’s disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies.

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

Cited by 14 publications

References 90 publications

Liuwei Dihuang formula ameliorates chronic stress-induced emotional and cognitive impairments in mice by elevating hippocampal O-GlcNAc modification

Liuwei Dihuang formula ameliorates chronic stress-induced emotional and cognitive impairments in mice by elevating hippocampal O-GlcNAc modification

Protective Effect of SGLT2 Inhibitor on D-Galactose-Induced Senescence in Mice and Its Mechanism

Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

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