Oncotarget: Modulating Tau Post-translational modifications and cytoskeletal network


Oncotarget published "Epigallocatechin-3-gallate modulates Tau Post-translational modifications and cytoskeletal network" which reported that the chemical modulators of Tau PTMs, such as kinase inhibitors and antibody-based therapeutics, have been developed, but natural compounds, as modulators of Tau PTMs are not much explored.

These authors applied biophysical and biochemical techniques like fluorescence kinetics, oligomerization analysis and transmission electron microscopy to investigate the impact of EGCG on Tau glycation in vitro.

EGCG inhibited methyl glyoxal -induced Tau glycation in vitro.

EGCG potently inhibited MG-induced advanced glycation endproducts formation in neuroblastoma cells as well modulated the localization of AT100 phosphorylated Tau in the cells.

They report EGCG, a green tea polyphenol, as a modulator of in vitro methylglyoxal-induced Tau glycation and its impact on reducing advanced glycation end products in neuroblastoma cells.

EGCG, a green tea polyphenol, as a modulator of in vitro methylglyoxal-induced Tau glycation and its impact on reducing advanced glycation end products in neuroblastoma cells.

Dr. Subashchandrabose Chinnathambi from The CSIR-National Chemical Laboratory as well as The Academy of Scientific and Innovative Research said, "Tau is a microtubule-associated protein, which aids in neuronal functioning [1, 2] and Tau neurofibrillary tangles is one of the important characteristic pathology in AD."

The clearance of hyperphosphorylated Tau is decreased by PTMs like glycation, nitration and polyamination whereas glycosylation and dephosphorylation prevents Tau hyperphosphorylation.

Glycation, unlike phosphorylation, is a non-enzymatic PTM, occurring between reducing sugars and protein, lipids etc. Glycation is triggered in presence of high blood sugar levels due to their metabolism via polyol pathway, which converts sugars into highly reactive intermediates like methyl glyoxal, gloxal etc. Glycation involves multistep reactions including complex re-arrangements forming advanced glycation end products .

Moreover, Tau glycation is modulated in an isoform-dependent manner and glycation along with phosphorylation increases the aggregation propensity of full-length Tau.

In this study, they demonstrate the effect of EGCG in inhibiting Tau glycation in vitro and global glycation in the neuroblastoma cells.

Figure 10: EGCG maintains neuronal cell cytoskeleton integrity.

Figure 10: EGCG maintains neuronal cell cytoskeleton integrity. Methyl glyoxal treatment leads to glycation of actin and microtubules leading to hampered growth of neuritic extensions and microtubule organization. Microtubule stabilization by +TIP EB1 is also affected resulting in loss of cell morphology. In presence of EGCG, the actin rich neuritic extensions are enhanced which might help in neuronal connections. EGCG also maintains intact MTOC and thus microtubule mediated transport. EGCG also helps in microtubule polymerization via EB1 protein thus maintaining and rescuing overall cell integrity.

The Chinnathambi Research Team concluded in their Oncotarget Research Output that similar studies have reported decrease in MG-induced AGEs formation in neuro2a by AG.

The decrease in AGEs and ROS by EGCG has already been shown by previous studies via Nrf2 -dependent pathways in various cell types.

The exact mechanism of inhibiting AGEs formation in mouse neuroblastoma cells is unclear but it might be due to the quenching of carbonyls formed during glycation by EGCG.

EGCG was found to reduce the glycation of cytoskeletal elements like actin and tubulin.

Reduced glycation was accompanied with resumed tubulin assembly and enhanced actin extensions thus improving neuronal structural integrity.

DOI - https://doi.org/10.18632/oncotarget.27963

Full text - https://www.oncotarget.com/article/27963/text/

Correspondence to - Subashchandrabose Chinnathambi - [email protected]

Keywords - Alzheimer's disease, Tau protein, Tau PTMs, Tau glycation, Tau glycation inhibition

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