Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy

Graham, Danielle; Gray, Audrey; Joyce, John A.; Yu, Dongzi; O’Moore, Jill; Carlson, George A.; Shearman, Mark S.; Dellovade, Tammy L.; Hering, Heike

doi:10.1016/j.neuropharm.2013.11.025

Cited by 94 publications

(106 citation statements)

References 21 publications

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“…Accordingly, decreased O-GlcNAc may thus contribute to the propagation of toxic species in the brain and enable the spread of these hallmark pathologies within the AD brain. Nevertheless, regardless of the precise mechanisms that are operative, the consistent lack of apparent toxicity of OGA inhibitors (48,78,86,94,95,100), coupled with the clear protective effects of perturbing O-GlcNAc cycling, suggests that OGA inhibitors are a promising potential disease-modifying monotherapy for AD and other tauopathies. Such compounds may represent an opportunity to positively influence the toxicity associated with both tau and A␤ and accordingly alter the course of both hallmark pathologies of AD.…”

Section: Resultsmentioning

confidence: 99%

“…The neuron-specific deletion of the gene encoding OGT in mice causes increased tau phosphorylation (57). Using the selective OGA inhibitor Thiamet-G, which increases brain O-GlcNAcylation (47), Yuzwa et al (78) found that acute OGA inhibition decreases tau phosphorylation at several pathologically relevant residues, an observation recently replicated by researchers at EMD Serono (48).…”

Section: Tau O-glcnacylation In Admentioning

confidence: 98%

See 1 more Smart Citation

The Emerging Link between O-GlcNAc and Alzheimer Disease

Zhu

Shan²,

Yuzwa³

et al. 2014

Journal of Biological Chemistry

227

173

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Section: Resultsmentioning

confidence: 99%

Section: Tau O-glcnacylation In Admentioning

confidence: 98%

The Emerging Link between O-GlcNAc and Alzheimer Disease

Zhu

Shan²,

Yuzwa³

et al. 2014

Journal of Biological Chemistry

227

173

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“…Tau-targeted drugs for AD therapy under development include Hsp90 inhibitors to degrade hyperphosphorylated tau [37], tau aggregation inhibitors such as methylthioninium chloride and methylthioninium [38], O-GlcNAcase inhibitors to prevent tau phosphorylation and aggregation [39], inhibitors of tau fibrillization [40], and microtubule stabilizing agents [41]. In a series of our studies, DCP-LA induces a long-lasting facilitation of hippocampal synaptic transmission by stimulating vesicular transport of α7 ACh receptor, involving release of neurotransmitters including glutamate, and AMPA receptor, involving excitatory synaptic transmission, toward presynaptic terminals and postsynaptic cells, respectively [42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

et al. 2015

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Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.

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“…In vitro , O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) at S400 was inversely correlated with tau phosphorylation at S396 (Smet-Nocca et al, 2011). However, treatment of tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAcylation, hindered the formation of tau aggregates, and slowed neurodegeneration without affecting the phosphorylation of tau (Yuzwa et al, 2012; Graham et al, 2013). …”

Section: Tau Phosphorylation In Alzheimer's Disease and Other Tauopatmentioning

confidence: 99%

Protein phosphorylation in neurodegeneration: friend or foe?

Tenreiro¹,

Eckermann

Outeiro

2014

Front. Mol. Neurosci.

219

197

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Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.

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Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy

Cited by 94 publications

References 21 publications

The Emerging Link between O-GlcNAc and Alzheimer Disease

The Emerging Link between O-GlcNAc and Alzheimer Disease

Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

Protein phosphorylation in neurodegeneration: friend or foe?

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