@article {44532, title = {Multi-faceted role of melatonin in neuroprotection and amelioration of tau aggregates in alzheimer{\textquoteright}s disease}, journal = {Journal of Alzheimers Disease}, volume = {62}, year = {2018}, month = {MAY}, pages = {1481-1493}, abstract = {

Alzheimer{\textquoteright}s disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-beta plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin{\textquoteright}s pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-beta needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

}, keywords = {Alzheimer{\textquoteright}s disease, hyperphosphorylation, melatonin, mitochondria, Protein aggregation, tau protein}, issn = {1387-2877}, doi = {10.3233/JAD-170900}, author = {Balmik, Abhishek Ankur and Chinnathambi, Subashchandrabose} } @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 {47005, title = {Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia}, journal = {Journal of Neuroinflammation}, volume = {17}, year = {2020}, month = {JAN }, pages = {10}, type = {Article}, abstract = {

Background Alzheimer{\textquoteright}s disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-beta plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. Methods In this study, we have prepared and stabilized hTau40(WT) oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1-sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-beta sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40(WT) oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. Results Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11(+) Iba1(high) microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. Conclusion The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer{\textquoteright}s disease condition.

}, keywords = {Actin, activation, Alzheimer{\textquoteright}s disease, microglia, migration, neurodegeneration, Tau Oligomers, Tauopathy}, doi = {10.1186/s12974-019-1694-y}, author = {Das, Rashmi and Balmik, Abhishek Ankur and Chinnathambi, Subashchandrabose} }