02440nas a2200229 4500008004100000022001400041245007500055210006900130260000800199520163100207653002401838653003301862653004501895653001901940653002801959653000801987653002001995653003202015100002802047700003602075856009902111 2020 eng d a0272-434000aAutophagic pathways to clear the tau aggregates in alzheimer's disease0 aAutophagic pathways to clear the tau aggregates in alzheimers di cJUN3 a

Tau is a microtubule-associated protein with an intrinsically unstructured conformation. Tau is subjected to several pathological post-translational modifications (PTMs), leading to its loss of interaction with microtubules and accumulation as neurofibrillary tangles (NFTs) in neurons. Tau aggregates impede functions of endoplasmic reticulum and mitochondria leading to the generation of oxidative stress and in turn amplifying the Tau aggregation. Tau is channelled to chaperones for folding into their native form, which otherwise causes its degradation and clearance. Cellular response triggers the activation of ubiquitin-proteasome system or autophagy to facilitate Tau degradation, based on the PTMs or mutations associated with Tau. Further, autophagy can be selective where Hsc70 interacts with Tau in monomeric, oligomeric and aggregated form and drives its clearance by chaperone-mediated autophagy pathway (CMA). Lysosome-associated membrane proteins-2A (LAMP-2A) is the key player of CMA that recognises Hsc70-Tau complex and triggers the downstream cascade. Thus, it becomes challenging for mutant Tau to be cleared by CMA as it loses its affinity for Hsc70 and LAMP-2A. In such a scenario, Tau might be degraded by macroautophagy otherwise sequestered by aggresomes. Henceforth, the degradation of Tau and its blockage that is associated with various PTMs of Tau would explain the dynamics of Tau degradation or accumulation in AD. Further, unveiling the role of accessory proteins involved in these degradation pathways would help in understanding their loss of function and preventing Tau clearance.

10aAlzheimer's disease10aChaperone-mediated autophagy10aLysosome-associated membrane proteins-2A10aMacroautophagy10aNeurofibrillary tangles10aTau10aTau degradation10aUbiquitin-proteasome system1 aGorantla, Nalini, Vijay1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/autophagic-pathways-clear-tau-aggregates-alzheimers-disease02066nas a2200277 4500008004100000022001400041245010400055210006900159260000800228300001100236490000900247520113900256653002401395653001901419653001401438653002901452653001601481653001601497100002801513700001601541700001601557700002801573700002601601700003601627856012501663 2020 eng d a0304-416500aMelatonin interacts with repeat domain of Tau to mediate disaggregation of paired helical filaments0 aMelatonin interacts with repeat domain of Tau to mediate disaggr cMAR a1294670 v18643 a

Tau is the major neuronal protein involved in the stabilization of microtubule assembly. In Alzheimer'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.

10aAlzheimer's disease10aDisaggregation10amelatonin10aPaired helical filaments10atau protein10aTauopathies1 aBalmik, Abhishek, Ankur1 aDas, Rashmi1 aDangi, Abha1 aGorantla, Nalini, Vijay1 aMarelli, Udaya, Kiran1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/melatonin-interacts-repeat-domain-tau-mediate-disaggregation-paired-helical-filaments01956nas a2200253 4500008004100000022001400041245007600055210006900131260000900200300001400209490000800223520116500231653001601396653002401412653001101436653001501447653002001462653000801482100002801490700001601518700002501534700003601559856010701595 2020 eng d a0141-813000aTransition metal nickel prevents Tau aggregation in Alzheimer's disease0 aTransition metal nickel prevents Tau aggregation in Alzheimers d cAUG  a1359-13650 v1563 a

Alzheimer's disease is the leading cause of dementia, effecting majority of aged people worldwide. The multifaceted effectors of Alzheimer's disease primarily include Tau, amyloid-beta along with hyper activation of kinases, oxidative stress and mutations etc., makes it challenging to design therapeutics. Tau is a microtubule-associating protein, which is subjected to cellular stress resulting in the formation of neurofibrillary tangles, leading to loss of affinity for microtubules. This causes loss of microtubule stability and in turn alters axonal integrity. In the present work, emphasis towards understanding interaction of nickel with Tau was made. Metals such as iron, zinc, copper and lead etc., are known to modulate Tau conformation and enhance its aggregation. Our results showed the deliverance of Tau aggregation by nickel and its synthetic morpholine conjugate. Nickel prevents aggregation by inducing degradation of Tau as evidenced by SDS-PAGE and TEM. Nickel and the synthetic conjugate being non toxic to neuro2a cells and prevent Tau aggregation, might direct these complexes to overcome AD. (C) 2019 Published by Elsevier B.V.

10aAggregation10aAlzheimer's disease10ametals10aMorpholine10aNickel chloride10aTau1 aGorantla, Nalini, Vijay1 aDas, Rashmi1 aBalaraman, Ekambaram1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/transition-metal-nickel-prevents-tau-aggregation-alzheimers-disease