02005nas a2200133 4500008004100000245007900041210006900120260001300189300001200202520148000214100002701694700003601721856011401757 2020 eng d00aProtein misfolding and aggregation of tau protein in alzheimer’s disease0 aProtein misfolding and aggregation of tau protein in alzheimer s bSpringer a139-1463 a

Protein misfolding has interestingly been referred to as the ‘dark side’ of the protein world. The cytotoxicity of misfolded and unfolded polypeptides is due to an overwhelmed quality control system, mainly comprising molecular chaperones to assist in folding, the unfolded protein response (UPR) in the endoplasmic reticulum and the heat shock response (HSR) in the cytosol, which are aimed at clearing misfolded proteins and their early aggregates. When misfolded/unfolded polypeptides exceed the quality control measures of the chaperone–ubiquitin–proteasome clearing system, they form toxic pre-fibrillar aggregates which interact with the cell membrane, disrupting redox potential due to aggregate organization into non-specific membrane pores. In most cases, increases in intracellular free Ca²⁺ and consequent disruption of the redox potential are among the earliest biochemical alterations in exposed cells. An improved understanding of the mechanisms of protein misfolding and intermediate structures that lead from monomers to oligomers ready to aggregate could provide crucial impetus to therapeutic interventions such as upregulating molecular chaperone machinery, use of antibodies and high throughput screening of promising candidate molecules.

1 aChandrashekar, Madhura1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/protein-misfolding-and-aggregation-tau-protein-alzheimer%E2%80%99s-disease02238nas a2200217 4500008004100000022001400041245008900055210006900144260000800213520145500221653002401676653002501700653001601725653001401741653002901755100002501784700003401809700002701843700003601870856011401906 2020 eng d a0272-434000aRole of microglia in regulating cholesterol and tau pathology in alzheimer's disease0 aRole of microglia in regulating cholesterol and tau pathology in cMAY3 a

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's disease. Thus, in order to regulate the pathogenesis of Alzheimer'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.

10aAlzheimer's disease10aAmyloid-beta protein10aCholesterol10amicroglia10aTau hyperphosphorylation1 aNanjundaiah, Shwetha1 aChidambaram, Hariharakrishnan1 aChandrashekar, Madhura1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/role-microglia-regulating-cholesterol-and-tau-pathology-alzheimers-disease02240nas a2200277 4500008004100000022001400041245007900055210006900134260000800203300001100211490000800222520137500230653002001605653001501625653000901640653002201649653001101671653002001682653002401702100001801726700002101744700002301765700002701788700003601815856011101851 2023 eng d a0141-813000aBacopa monnieri reduces Tau aggregation and Tau-mediated toxicity in cells0 aBacopa monnieri reduces Tau aggregation and Taumediated toxicity cAPR a1231710 v2343 a

Alzheimer's disease is a neurodegenerative disease characterized by progressive memory loss and behavioral impairments. In the present study, the ethanolic extract of Bacopa monnieri was studied for its potency to inhibit Tau aggregation and rescuing of the viability of Tau-stressed cells. Bacopa monnieri was observed to inhibit the Tau aggregation in vitro. The cells exposed to Bacopa monnieri were also observed to have a low level of ROS and caspase-3 activity. The immunoblot and immunofluorescence analysis showed that Bacopa monnieri acts as an antioxidant and restored the Nrf2 levels in Neuro2a cells. Bacopa monnieri treatment to Neuro2a cells was observed to reduce the phospho-Tau load in formaldehyde-stressed cells. Furthermore, the treatment of Bacopa monnieri reduced the phosphorylation of GSK-3 beta in formaldehyde-stressed cells. Ran and NUP358 are the key proteins involved in nuclear transport. It was observed that formaldehyde treatment impaired the nuclear transport by missorting the NUP358 arrangement in Neuro2a cells. On the contrary, Bacopa monnieri treatment restored the NUP358 arrangement in cells. The overall results of the present study suggested that Bacopa monnieri could be considered a potent herb against Tau phosphorylation and Tau aggregation, which projects it as a promising formulation for Alzheimer's disease.

10aBacopa monnieri10aGSK-3 beta10aNrf210aNuclear transport10aNUP35810aTau Aggregation10aTau phosphorylation1 aDubey, Tushar1 aKushwaha, Preeti1 aThulasiram, H., V.1 aChandrashekar, Madhura1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/bacopa-monnieri-reduces-tau-aggregation-and-tau-mediated-toxicity-cells02225nas a2200241 4500008004100000022001400041245010200055210006900157260000800226490000800234520137900242653001601621653001301637653002001650653002001670100001801690700002901708700002801737700002401765700002701789700003601816856013101852 2023 eng d a0927-776500aInhibitory effect of curcumin-artemisinin co-amorphous on Tau aggregation and Tau phosphorylation0 aInhibitory effect of curcuminartemisinin coamorphous on Tau aggr cJAN0 v2213 a

Tau is a natively unfolded microtubule-associated protein. Tau neurofibrillary tangles are one of the hallmarks of Alzheimer's disease. The post-translational modifications of Tau lead to its pathological state. Phosphorylation is the key post-translational modification associated with Tauopathy. Curcumin is a polyphenolic compound pre-sent in the rhizomes of Curcuma longa. Curcumin has been reported to have remarkable medicinal properties in several diseases, but its poor solubility limits its therapeutic potency. Artemisinin is a sesquiterpene lactone, which has been known sience ancient times for its applications as a treatment for various diseases such as malaria, cancer, autoimmune disease, etc. In the present study, the potency of crystalline curcumin, crystalline artemisinin, and Cur-Art co-amorphous dispersion were evaluated against Tau pathology. The in-vitro ThS/ANS fluorescence and electron microscopy results suggested that curcumin and Cur-Art efficiently inhibited Tau aggregation. Furthermore, exposure to curcumin and Cur-Art co-amorphous restored the impaired nuclear transport in formaldehyde-stressed cells. Curcumin was also found to modulate the phosphorylation of Tau, which indicated the neuroprotective potency. Thus, curcumin and Cur-Art co-amorphous exhibit therapeutic potential against Tau protein in Alzheimer's disease.

10aartemisinin10acurcumin10aPhosphorylation10aTau Aggregation1 aDubey, Tushar1 aSonawane, Shweta, Kishor1 aMannava, M., K. Chaitan1 aNangia, Ashwini, K.1 aChandrashekar, Madhura1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/inhibitory-effect-curcumin-artemisinin-co-amorphous-tau-aggregation-and-tau-phosphorylation06699nas a2200169 4500008004100000245010700041210006900148260000800217520600300225100003606228700002906264700002706293700003406320700002606354700002506380856012406405 2024 eng d00aDual modification of tau by pseudophosphorylation and glycation does not enhance amorphous aggregation0 aDual modification of tau by pseudophosphorylation and glycation  cAPR3 a

Background/Aims:

 The neurofibrillary tangles consisting of Tau protein are an important pathology in Alzheimer’s disease. The paired helical filaments of Tau form most of the NFTs. These PHFs of Tau are found to carry numerous post-translational modifications, which stabilize them and aid in aggregation. The mechanistic function of Tau is to bind and stabilize the axonal microtubules. Hyperphosphorylation of Tau causes it to compromise its physiological function and accumulate in the neurons in the form of aggregates. Such residue-specific phosphorylation has been studied by employing Tau pseudophosphorylation mutants. But in addition to phosphorylation, several other modifications also aid in stabilizing the Tau PHF. Glycation is one such non-enzymatic PTM caused by sugars and their reactive intermediates. In this study, we employed the pseudophosphorylated Tau double mutants (262/404D, 262/396D, and 231/262) for studying their modification by methyl glyoxal, a reactive intermediate of glucose metabolism. 

Methods:

 We studied various biophysical properties like aggregation propensity, Advanced glycation end-product formation, and global conformation of the Tau with dual modifications. Our study includes the use of in vitro techniques e.g., ThS fluorescence assay, electron microscopy, CD spectroscopy, SDS-PAGE. 

Results:

 The overall result of the study suggest that the MG-induced Tau aggregation is influenced by the residue-specific Tau phosphorylation. 

Conclusion:

 In conclusion, the combinatorial effect of discreet PTMs on Tau function could lead to a better understanding of Tauopathy.

1 aChinnathambi, Subashchandrabose1 aSonawane, Shweta, Kishor1 aChandrashekar, Madhura1 aChidambaram, Hariharakrishnan1 aThulasiram, Shrivatsa1 aKulkarni, Mahesh, J. uhttps://library.ncl.res.in/content/dual-modification-tau-pseudophosphorylation-and-glycation-does-not-enhance-amorphous