@article {46842, title = {Effect of melatonin on tau aggregation and tau-mediated cell surface morphology}, journal = {International Journal of Biological Macromolecules}, volume = {152}, year = {2020}, month = {JUN }, pages = {30-39}, type = {Article}, abstract = {

Aggregation of Microtubule-associated protein Tau and its deposition in the form of neurofibrillary tangles (NFTs) is one of the pathological hallmarks of Alzheimer{\textquoteright}s disease (AD). Tau aggregation inhibition has been targeted in various studies including natural compounds and synthetic small molecules. Here, we have studied neurohormone- Melatonin against in vitro Tau aggregation and observed its effect on membrane topology, tubulin network and Tau phosphorylation in Neuro2A and N9 cell lines. The aggregation and conformation of Tau was determined by ThT fluorescence and CD spectroscopy respectively. The morphology of Tau aggregates in presence and absence of Melatonin was studied by transmission electron microscopy. Melatonin was found to reduce the formation of higher order oligomeric structures without affecting the overall aggregation kinetics of Tau. Melatonin also modulates and helps to maintain membrane morphology, independent on tubulin network as evidenced by FE-SEM and immunofluorescence analysis. Overall, Melatonin administration shows mild anti-aggregation and cytoprotective effects. (C) 2020 Elsevier B.V. All rights reserved.

}, keywords = {Alzheimer{\textquoteright}s disease, Cell surface morphology, melatonin, Paired helical filaments, tau protein, Tauopathies}, issn = {0141-8130}, doi = {10.1016/j.ijbiomac.2020.01.296}, author = {Das, Rashmi and Balmik, Abhishek Ankur and Chinnathambi, Subashchandrabose} } @article {46945, title = {Melatonin interacts with repeat domain of Tau to mediate disaggregation of paired helical filaments}, journal = {Biochimica Et Biophysica Acta-General Subjects}, volume = {1864}, year = {2020}, month = {MAR}, pages = {129467}, type = {Article}, abstract = {

Tau is the major neuronal protein involved in the stabilization of microtubule assembly. In Alzheimer{\textquoteright}s disease, Tau self-assembles to form intracellular protein aggregates which are toxic to cells. Various methods have been tried and tested to restrain the aggregation of Tau. Most of the agents tested for this purpose have limitations in their effectiveness and availability to neuronal cells. We have tested melatonin, a neurohormone secreted by pineal gland and a well-known anti-oxidant, for its ability to interact with the repeat domain of Tau using ITC and NMR. In aggregation inhibition and disaggregation studies of repeat Tau, melatonin was found to modulate the aggregation propensity of repeat Tau at a concentration of 5000 mu M and was more effective in dissolving preformed aggregates rather than acting as an aggregation inhibitor. However, there were no major conformational changes in Tau in presence of melatonin as observed by CD spectroscopy. On the basis of our findings, we are proposing a mechanism by which melatonin can interact with the repeat domain of Tau and exhibit its disaggregation effect.

}, keywords = {Alzheimer{\textquoteright}s disease, Disaggregation, melatonin, Paired helical filaments, tau protein, Tauopathies}, issn = {0304-4165}, doi = {10.1016/j.bbagen.2019.129467}, author = {Balmik, Abhishek Ankur and Das, Rashmi and Dangi, Abha and Gorantla, Nalini Vijay and Marelli, Udaya Kiran and Chinnathambi, Subashchandrabose} } @article {46613, title = {Melatonin reduces GSK3 beta-mediated tau phosphorylation, enhances Nrf2 nuclear translocation and anti-inflammation}, journal = {ASN Neuro}, volume = {12}, year = {2020}, month = {DEC}, pages = {1759091420981204}, type = {Article}, abstract = {

Alzheimer{\textquoteright}s disease is a neuropathological condition with abnormal accumulation of extracellular Amyloid-beta plaques and intracellular neurofibrillary tangles of Microtubule-associated protein Tau (Tau) in the brain. In pathological conditions, Tau undergoes post-translational modifications such as hyperphosphorylation by the activity of cellular kinases, which eventually leads to protein aggregation in neurons. Melatonin is a neuro-hormone that is mainly secreted from the pineal gland and functions to modulate the cellular kinases. In our study, we have checked the neuroprotective function of Melatonin by MTT and LDH assay, where Melatonin inhibited the Tau aggregates-mediated cytotoxicity and membrane leakage in Neuro2A cells. The potency of Melatonin has also been studied for the quenching of intracellular reactive oxygen species level by DCFDA assay and caspase 3 activity. Melatonin was shown to reduce the GSK3 beta mRNA and subsequent protein level as well as the phospho-Tau level (pThr181 and pThr212-pSer214) in okadaic acid-induced Neuro2A cells, as observed by western blot and immunofluorescence assay. Further, Melatonin has increased the cellular Nrf2 level and its nuclear translocation as an oxidative stress response in Tauopathy. The Melatonin was found to induce pro- and anti-inflammatory cytokines levels in N9 microglia. The mRNA level of cellular kinases such as as-GSK3 beta, MAPK were also studied by qRT-PCR assay in Tau-exposed N9 and Neuro2A cells. The immunomodulatory effect of Melatonin was evident as it induced IL-10 and TGF-beta cytokine levels and activated MAP3K level in Tau-exposed microglia and neurons, respectively. Melatonin also downregulated the mRNA level of pro-inflammatory markers, IL-1 beta and Cyclooxygenase-2 in N9 microglia. Together, these findings suggest that Melatonin remediated the cytokine profile of Tau-exposed microglia, reduced Tau hyperphosphorylation by downregulating GSK3 beta level, and alleviated oxidative stress via Nrf2 nuclear translocation.

}, keywords = {Alzheimer\&\#8217, Anti-inflammatory, GSK3\&\#946, melatonin, microglia, neurodegeneration, Nrf2, s disease, Tau hyperphosphorylation}, issn = {1759-0914}, doi = {10.1177/1759091420981204}, author = {Das, Rashmi and Balmik, Abhishek Ankur and Chinnathambi, Subashchandrabose} }