Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors

Lim, Sungsu; Haque, Md. Mamunul; Nam, Ghilsoo; Ryoo, Nayeon; Rhim, Hyewhon; Kim, Yun Kyung

doi:10.3390/ijms160920212

Cited by 40 publications

(31 citation statements)

References 22 publications

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“…GH84 human O -GlcNAcase (hOGA) catalyzes the removal of O -GlcNAc from serine or threonine residues in glycoproteins, and has been found to link to Alzheimer’s disease (AD) 11 . Evidences have shown that AD is closely associated with tau hyperphosphorylation in patient’s brain, while such site remains protected by O -GlcNAc in a healthy neuron 12 . Thus, human O -GlcNAcase inhibitors that block tau hyperphosphorylation can help in the treatments of AD 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors.

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Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…For example, Thiamet-G stimulates autophagy through a mammalian target of rapamycin-independent pathway in neuroblastoma N2a cells, primary rat neurons and mouse brain, which helps the brain to combat the accumulation of toxic protein species [ 115 ]. Besides the pharmacological inhibition of OGA, BZX2, an OGT inhibitor, leads to a 2-fold increase in tau phosphorylation at Ser199 and 1.5-fold increase at Ser396 inducing tau aggregation [ 41 ].…”

Section: Glycosylation In Alzheimer’s Diseasementioning

confidence: 99%

The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

Bukke

Villani

Moola

et al. 2020

IJMS

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Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer’s disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset cases. A decrease in availability of glucose content induces a considerable impairment/downregulation of glycosylation, which is an important post-translational modification. Glycosylation is an important and highly regulated mechanism of secondary protein processing within cells and it plays a crucial role in modulating stability of proteins, as carbohydrates are important in achieving the proper three-dimensional conformation of glycoproteins. Moreover, glycosylation acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. All the proteins involved in β-amyloid (Aβ) precursor protein metabolism have been identified as candidates of glycosylation highlighting the possibility that Aβ metabolism could be regulated by their glycosylation. Within this framework, the present review aims to summarize the current understanding on the role of glycosylation in the etiopathology of AD, emphasizing the idea that glucose metabolic pathway may represent an alternative therapeutic option for targeting AD. From this perspective, the pharmacological modulation of glycosylation levels may represent a ‘sweet approach’ to treat AD targeting new mechanisms independent of the amyloid cascade and with comparable impacts in familial and sporadic AD.

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“…We exposed tau-aggregation sensor cells, named tau-bimolecular fluorescence complementation (tau-BiFC) to conditioned media collected from five different glioblastoma cells (A172, HS683, U87, U373, and T98G) (Fig. 2a ) 19 , 25 , 26 . Tau-BiFC cells are HEK293-derived stable cell line, which constitutively expresses tau-BiFC vectors.…”

Section: Glioblastoma-secretome Activates Tau Hyper-phosphorylation Amentioning

confidence: 99%

Glioblastoma-secreted soluble CD44 activates tau pathology in the brain

Lim

Kim

et al. 2018

Exp Mol Med

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During aggressive tumor growth and migration, glioblastoma cells secrete diverse molecules and adhesion proteins to the extracellular matrix. Yet, the biochemical effects of the glioblastoma secretome in the brain remain largely unknown. Here we show that soluble CD44 secreted from glioblastoma cells induces neuronal degeneration through the activation of tau pathology in the brain. Glioblastoma-xenograft tissues showed a number of degenerating neurons bearing highly phosphorylated tau. Through a series of secretome-analyses, we identified that soluble CD44 was the responsible protein inducing tau phosphorylation and aggregation (EC50 = 19.1 ng/mL). The treatment of sCD44 to primary hippocampal neurons-induced tau hyperphosphorylation, leading to neuronal degeneration. Also, the injection of sCD44 into the brains of tau transgenic mice induced tau hyper-phosphorylation in hippocampal neurons. Altogether, our data suggest a neurodegenerative role of sCD44 in promoting tau pathology and serving as a molecular link between glioblastoma and neurodegeneration.

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Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors

Cited by 40 publications

References 22 publications

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

Glioblastoma-secreted soluble CD44 activates tau pathology in the brain

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