@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 = {<p>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.</p>
},
	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}
}
@article {46847,
	title = {Role of microglia in regulating cholesterol and tau pathology in alzheimer{\textquoteright}s disease},
	journal = {Cellular and Molecular Neurobiology},
	year = {2020},
	month = {MAY},
	type = {Review; Early Access 2020},
	abstract = {<p>Cholesterol, a principal constituent of the cell membrane, plays a crucial role in the brain by regulating the synaptic transmission, neuronal signaling, as well as neurodegenerative diseases. Defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-beta protein. Tau, a major microtubule-associated protein in the brain, is the key regulator of the mature neuron. Abnormally hyperphosphorylated Tau hampers the major functions related to microtubule assembly by promoting neurofibrillary tangles of paired helical filaments, twisted ribbons, and straight filaments. The observed pathological changes due to impaired cholesterol and Tau protein accumulation cause Alzheimer{\textquoteright}s disease. Thus, in order to regulate the pathogenesis of Alzheimer{\textquoteright}s disease, regulation of cholesterol metabolism, as well as Tau phosphorylation, is essential. The current review provides an overview of (1) cholesterol synthesis in the brain, neurons, astrocytes, and microglia; (2) the mechanism involved in modulating cholesterol concentration between the astrocytes and brain; (3) major mechanisms involved in the hyperphosphorylation of Tau and amyloid-beta protein; and (4) microglial involvement in its regulation. Thus, the answering key questions will provide an in-depth information on microglia involvement in managing the pathogenesis of cholesterol-modulated hyperphosphorylated Tau protein.</p>
},
	keywords = {Alzheimer{\textquoteright}s disease, Amyloid-beta protein, Cholesterol, microglia, Tau hyperphosphorylation},
	issn = {0272-4340},
	doi = {10.1007/s10571-020-00883-6},
	author = {Nanjundaiah, Shwetha and Chidambaram, Hariharakrishnan and Chandrashekar, Madhura and Chinnathambi, Subashchandrabose}
}
