03043nas a2200253 4500008004100000245008900041210006900130260000900199300000700208490000700215520224100222653001002463653001502473653002402488653001402512653001402526653002202540653001802562653001402580100001602594700002802610700003602638856011502674 2020 eng d00aPhagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia0 aPhagocytosis of fulllength Tau oligomers by Actinremodeling of a cJAN  a100 v173 a

Background Alzheimer'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's disease condition.

10aActin10aactivation10aAlzheimer's disease10amicroglia10amigration10aneurodegeneration10aTau Oligomers10aTauopathy1 aDas, Rashmi1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/phagocytosis-full-length-tau-oligomers-actin-remodeling-activated-microglia02652nas a2200277 4500008004100000245011100041210006900152260000900221300000700230490000700237520177100244653001002015653001702025653001002042653001602052653002202068653002002090653001202110653001402122653000802136653001602144100002802160700002902188700003602217856012102253 2021 eng d00aExtracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau0 aExtracellular HDAC6 ZnF UBP domain modulates the actin network a cMAY  a490 v193 a

Background: Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein. Methods: Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3 beta regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization. Results: HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3 beta increases without any change in total GSK-3 beta level. Conclusions: HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases.

10aActin10aCytoskeleton10aHDAC610aMicrotubule10aneurodegeneration10aPhosphorylation10aPodonut10aPodosomes10aTau10aTauopathies1 aBalmik, Abhishek, Ankur1 aSonawane, Shweta, Kishor1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/extracellular-hdac6-znf-ubp-domain-modulates-actin-network-and-post-translational01857nas a2200241 4500008004100000022001400041245008900055210006900144260000800213300001200221490000700233520106600240653001001306653001901316653002801335653002601363653002501389653001401414653001201428100001801440700003601458856012101494 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 uhttps://library.ncl.res.in/content/photodynamic-sensitizers-modulate-cytoskeleton-structural-dynamics-neuronal-cells01984nas a2200241 4500008004100000022001400041245007200055210006900127260000800196300001100204490000900215520126100224653001001485653001701495653001001512653001701522653001701539653000801556653001901564100002001583700003601603856010301639 2022 eng d a0167-488900aHistone deacetylase-6 modulates Tau function in Alzheimer's disease0 aHistone deacetylase6 modulates Tau function in Alzheimers diseas cAUG a1192750 v18693 a

Alzheimer's disease (AD), one of the major tauopathies, is multifactorial with a massive demand for disease modifying treatments rather than symptom management. An AD-affected neuron shows Tau depositions generated due to overload on the proteostasis machinery of the cell and/or abnormal post-translational modifications on Tau protein. Loss of memory or dementia is the most significant concern in AD, occurring due to the loss of neurons and the connections between them. In a healthy brain, neurons interact with the environment and each other through extensions and migratory structures. It can thus be safe to assume that Tau depositions affect these growth structures in neurons. A Histone Deacetylase, HDAC6, has shown elevated levels in AD while also demonstrating direct interaction with the Tau protein. HDAC6 interacts with multiple proteins in the cell and is possibly involved in various signalling pathways. Its deacetylase activity has been a point of controversy in AD; however other functional domains remain unexplored. This review highlights the beneficial potential of HDAC6 in AD in mediating both Tau proteostasis and cytoskeletal rewiring for the neuritic extensions through its Ubiquitin Binding domain (HDAC6 ZnF UBP).

10aActin10aCytoskeleton10aHDAC610aMicrotubules10aProteostasis10aTau10aZnF UBP domain1 aQureshi, Tazeen1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/histone-deacetylase-6-modulates-tau-function-alzheimers-disease01751nas a2200241 4500008004100000022001400041245009800055210006900153260000800222300001100230490000800241520096100249653001001210653001901220653002801239653001001267653001701277653001401294653001201308100002801320700003601348856012501384 2022 eng d a0171-933500aInter-relationship of Histone Deacetylase-6 with Tau-cytoskeletal organization and remodeling0 aInterrelationship of Histone Deacetylase6 with Taucytoskeletal o cAPR a1512020 v1013 aCytoskeletal elements are the key players in cellular integrity, structure, signalling and migration. Each cytoskeletal element comprises of properties with respect to its structure and stability, which serve a specific array of functions. These structures are highly dynamic and regulated by modulation via direct interaction or post-translational modifications. HDAC6 is a cytoplasmic deacetylase known to regulate a wide range of cellular functions either through its deacetylase activity or direct interaction via its C-terminal ZnF UBP domain. HDAC6 has been widely studied for its role in aggresome formation, which acts as a protective mechanism upon protein aggregation. HDAC6 is known to play a critical role in the regulation of cytoskeletal elements-microtubules and actin filaments. This review summarizes the regulatory role of HDAC6 in cytoskeletal remodeling and dynamics of neuronal cells and its significance in neurodegenerative diseases.10aActin10aCell migration10aCytoskeleton remodeling10aHDAC610aMicrotubules10aPodosomes10aZnF UBP1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/inter-relationship-histone-deacetylase-6-tau-cytoskeletal-organization-and-remodeling