02972nas a2200277 4500008004100000022001400041245012000055210006900175260000800244300002100252490000700273520204300280653002102323653002202344653001502366653001402381653001402395653002202409653000902431653001402440653002902454100001602483700002802499700003602527856013102563 2020 eng d a1759-091400aMelatonin reduces GSK3 beta-mediated tau phosphorylation, enhances Nrf2 nuclear translocation and anti-inflammation0 aMelatonin reduces GSK3 betamediated tau phosphorylation enhances cDEC a17590914209812040 v123 a

Alzheimer'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.

10aAlzheimer&\#821710aAnti-inflammatory10aGSK3&\#94610amelatonin10amicroglia10aneurodegeneration10aNrf210as disease10aTau hyperphosphorylation1 aDas, Rashmi1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose uhttp://library.ncl.res.in/content/melatonin-reduces-gsk3-beta-mediated-tau-phosphorylation-enhances-nrf2-nuclear-translocation02422nas a2200241 4500008004100000022001400041245012900055210006900184260000800253300001200261490000700273520160700280653002101887653001901908653001501927653001401942653001401956653001401970653001801984100001602002700003602018856012602054 2021 eng d a1398-921900aMicroglial remodeling of actin network by Tau oligomers, via G protein-coupled purinergic receptor, P2Y12R-driven chemotaxis0 aMicroglial remodeling of actin network by Tau oligomers via G pr cMAY a153-1700 v223 a

Alzheimer's disease (AD) is associated with age-related neurodegeneration, synaptic deformation and chronic inflammation mediated by microglia and infiltrated macrophages in the brain. Tau oligomers can be released from damaged neurons via various mechanisms such as exosomes, neurotransmitter, membrane leakage etc. Microglia sense the extracellular Tau through several cell-surface receptors and mediate chemotaxis and phagocytosis. The purinergic receptor P2Y12R recently gained interest in neurodegeneration for neuro-glial communication and microglial chemotaxis towards the site of plaque deposition. To understand the effect of extracellular Tau oligomers in microglial migration, the P2Y12R-mediated actin remodeling, reorientation of tubulin network and rate of migration were studied in the presence of ATP. The extracellular Tau species directly interacted with P2Y12R and also induced this purinoceptor expression in microglia. Microglial P2Y12R colocalized with remodeled membrane-associated actin network as a component of migration in response to Tau oligomers. As an inducer of P2Y12R, ATP facilitated the localization of P2Y12R in lamellipodia and filopodia during accelerated microglial migration. The direct interaction of extracellular Tau oligomers with microglial P2Y12R would facilitate the signal transduction in both way, directional chemotaxis and receptor-mediated phagocytosis. These unprecedented findings emphasize that microglia can modulate the membrane-associated actin structure and incorporate P2Y12R to perceive the axis and rate of chemotaxis in Tauopathy.

10aactin remodeling10aAlzheimer&apos10achemotaxis10amicroglia10amigration10as disease10aTau Oligomers1 aDas, Rashmi1 aChinnathambi, Subashchandrabose uhttp://library.ncl.res.in/content/microglial-remodeling-actin-network-tau-oligomers-g-protein-coupled-purinergic-receptor01856nas a2200241 4500008004100000022001400041245008900055210006900144260000800213300001200221490000700233520106600240653001001306653001901316653002801335653002601363653002501389653001401414653001201428100001801440700003601458856012001494 2021 eng d a1949-358400aPhotodynamic sensitizers modulate cytoskeleton structural dynamics in neuronal cells0 aPhotodynamic sensitizers modulate cytoskeleton structural dynami cJUN a232-2480 v783 a

The neuronal cytoskeleton plays a crucial role in maintaining cell integrity and functioning of neurons. Cytoskeleton deformities have been reported to be associated with neurodegenerative diseases thus; cytoskeleton can be targeted for therapeutic strategies. The therapeutic application of photosensitive molecule is termed as photodynamic therapy (PDT). PDT has been applied in the field of dermatology, cancer biology, and antimicrobial therapy. PDT induces several changes in cells, which include induction of apoptosis, DNA damage, and induction of inflammatory response. PDT has been also reported to modulate cytoskeleton such as actin dynamics. The in vitro studies suggested that PDT using dyes such as Toluidine Blue and Rose Bengal effectively modulated the actin cytoskeleton, neurite outgrowth, tubulin, and Tau aggregation. In this review, we focused on the effect of photosensitized molecules on various cytoskeleton proteins. We hypothesize that PDT could have potency against Alzheimer's disease and other neurodegenerative disorders.

10aActin10aAlzheimer&apos10acytoskeleton modulation10aneuronal cytoskeleton10aphotodynamic therapy10as disease10aTubulin1 aDubey, Tushar1 aChinnathambi, Subashchandrabose uhttp://library.ncl.res.in/content/photodynamic-sensitizers-modulate-cytoskeleton-structural-dynamics-neuronal-cells