Our work can be classified into three categories Biophysics, Biochemistry and Cellular Biophysics. 

 Tau structure and function

EGCG and Polyamines modulates Tau Post-translational modifications

Alzheimer’s disease is characterized by intracellular Tau tangles, one of the cause of neuronal degeneration. Post-translational modifications of Tau play a pivotal role in its pathogenesis and acts as a triggering factor in Tau aggregation (Gorantla and Chinnathambi, Journal of Molecular Neuroscience 2017, ACS Omega 2019 and ACS Omega 2020 and Sonawane and Chinnathambi, Journal of Molecular Neuroscience 2017, ACS Omega 2019 and ACS Omega 2020). Thus, Tau PTMs has become an important therapeutic target in AD. The chemical modulators of Tau PTMs such as kinase inhibitors and antibody based therapeutics have been developed (Sonawane and Chinnathambi, ABB, 2019). Natural compounds as modulators of Tau PTMs are yet to be explored. Here, we report EGCG, a green tea polyphenol, as a modulator of two key Tau PTMs, phosphorylation and glycation ((Sonawane and Chinnathambi, Journal of Alzheimers Disease, 2019, ACS Omega 2019). EGCG is found to modulate Tau phosphorylation and key kinase CDK5. EGCG is also found to inhibit Tau glycation in vitro and AGEs formation in the neuronal cells (Sonawane and Chinnathambi, Scientific Reports, 2020). EGCG was also found to localize AT100 phosphorylated Tau in the nucleus around the periphery of the nuclear membrane which was disturbed by Methylglyoxal. EGCG rescued and enhanced the neuritic extensions by preventing the glycation of actin cytoskeleton which was disrupted by glycating agent MG. Thus, EGCG alleviates the effect of Tau PTMs (Sonawane and Chinnathambi, bioRxiv, 2020). Polyamines are crucially important in modulating cell death and proliferation and are involved in disease conditions as well. The levels of polyamines are reduced in Alzheimer’s disease (AD) in region specific manner. We demonstrated the potency of polyamines; spermine and spermidine in inhibiting Tau aggregation in vitro by increasing the latency period of aggregation. Both the polyamines exhibited strong electrostatic interactions with repeat Tau (Sonawane and Chinnathambi, bioRxiv, 2020).

2. Melatonin Interacts with Repeat Domain of Tau to Mediate Disaggregation of Paired Helical Filaments

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 (Balmik and Chinnathambi, JAD, 2018). 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 and is more effective in dissolving preformed aggregates rather than acting as an aggregation inhibitor (Balmik and Chinnathambi, BBA, 2020). Melatonin Interacts with Repeat Domain of Tau to Mediate Disaggregation of Paired Helical Filaments. Melatonin exhibits a wide array of functions, which include free radical scavenging, anti-oxidant, anti-inflammatory function, immune modulation and metabolic regulation (Das and Chinnathambi, IJBIOMAC, 2020). In our study, we elucidated the neuroprotectant function of Melatonin by inhibiting Tau aggregates mediated cytotoxicity on Neuro2A cells. Further, Melatonin was found to increase Nrf2 level as oxidative stress response in Tau pathology. To evidence the immunomodulatory effect, we found that Melatonin has induced the IL-10 and TGF-β cytokine level and subsequently activates MAP3K level related to axonal repair in Tau overloaded microglia (Das and Chinnathambi, American Society of neuroscience, ASN Neuro, 2020).

3. HDAC6 ZnF UBP as the modifier of Tau structure and function

Histone deacetylase 6 is a class II histone deacetylase majorly present in the cytoplasm and involved in the regulation of various cellular functions. The interaction of HDAC6 ZnF UBP with Tau results in its degradation suggesting either proteolytic activity of HDAC6 ZnF UBP or its role in enhancing autoproteolysis of Tau (Balmik and Chinnathambi, Biochemistry, submitted, 2020). Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemistry. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases (Balmik and Chinnathambi, Under revision, 2020).

Internalization of Tau in Microglia and Astrocytes

4. Internalization of Tau in Microglia and Astrocytes

Microglial Priming of Antigen Presentation and Adaptive Stimulation in Alzheimer’s Diseases. The prominent pathological consequences of Alzheimer’s Disease (AD) are the misfolding and mis-sorting of two cellular proteins- Amyloid-β and microtubule associated protein Tau wherein accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of Amyloid-β associated signaling cascade and vice versa (Das and Chinnathambi, Cellular Molecular Life Sciences, 2019). In recent attention, neuroinflammation driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors, proves their diverse functions in maintaining CNS homeostasis via. collaboration with astrocytes and T-lymphocytes. Age related senescence or/and chronic inflammation activates microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis (Das and Chinnathambi, Journal of Neuroinflammation, 2020).

Lipid metabolism and GPCRs and related Tauopathy

5. Lipid metabolism in Tauopathy

Microglial polarization is an utmost important phenomenon in Alzheimer’s disease that influences the brain environment. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Omega-3 fatty acids have more influence on the brain and they found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells (Desale and Chinnathambi, Journal of Neuroinflammation, 2020). Tau seeds greatly contribute to the spread of disease; one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Our approach provides insights into the beneficial role of ALA as an anti-inflammatory dietary supplement to treat AD (Desale and Chinnathambi, bioRxiv and also in Journal of Neuroinflammation, submitted 2020). Extracellular Tau species are found to internalize more presence of ALA in microglia. The extensive polarization and migration was observed as indicated by extensive lamellipodia and filopodia formation. The actin dynamics supports the phagocytosis process (Desale and Chinnathambi, bioRxiv and also in iScience, submitted 2020).

Tau and GPCRs signaling

6. G-Protein Coupled Receptors and Tau-Different roles in Alzheimer’s disease

In Alzheimer’s disease, GPCRs are involved in phosphorylation of Tau through various downstream kinases such as GSK-3β, CDK-5 and ERKs signalling cascade. Several neuronal GPCRs that are involved in Tau phosphorylation are elaborated in this review. The astrocytic GPCR, Tau phosphorylation mediated by CaS receptors and its propagation by exosomes are also elaborated. In the microglia, the extra-cellular Tau binding to a chemokine GPCR, CX3CR1 triggers its internalization, whereas Tau phosphorylation at specific sites decreases its binding affinity to this receptor. (Chidambaram and Chinnathambi, Neuroscinece, 2020). Microglia is the main immune cell in the central nervous system, continuously surveilling synapses and pathogen invasion. The extracellular nucleotides released from damaged neurons and the cytokine-chemokine gradients allow the neighboring microglia and macrophages to migrate-infiltrate at the site of neuronal-damage. The P2Y receptors give ‘find me’ or ‘eat me’ signals to microglia to either migrate or phagocytose cellular debris. Further, the actin cytoskeleton helps microglia to mediate directed chemotaxis and neuronal repair during neurodegeneration. Hence, we aim to emphasize the connection between P2YR chemical signaling and actin-driven mechanical movements of microglia in AD (Das and Chinnathambi, Neuroscience, 2020). Purinergic receptor- P2Y12 were previously shown to be involved in microglial chemotaxis and got accumulated at the site of plaque depositions in AD brain. Microglial remodeling of actin network for P2Y12-mediated phagocytosis of Tau oligomers (Das and Chinnathambi, Revision, 2020).


Semster      Course       Title

Fall              NCL251       Advanced Techniques in Biology

Spring          NCL257      Cell Structure and Dynamics

Fall              NCL356       Introduction to Protein Misfolding Diseases



 1. 2017: Baicalein and EGCG as a potent inhibitors of Aggregation Inhibition in Alzheimer's disease. 2017-NF-0111.

Subashchandrabose Chinnathambi, Shweta Kishor Sonawane, Abhishek Balmik.

Provisional application filed (2017-NF-0111).

2. Molecular complexes for effective inhibition of Tau Aggregation

Subashchandrabose Chinnathambi, Balaraman Ekambaram, Nalini Vijay Gorantla, Siba P Modya.

Provisional application filed (2017-NF-0106), 201711019807.

3. Protein capped metal-based nanoparticles inhibits Tau Aggregation in vitro.

Subashchandrabose Chinnathambi, Shweta Kishor Sonawane.

Provisional application filed , 2017051831532.  

4. Inhibition and dissolution of Tau Aggregation by intermediate and final Limonoids in Alzheimer's disease.

Subashchandrabose Chinnathambi, Thulasiram HV, Nalini Vijay Gorantla, Fiyaz Mulani.

Disclosure number: 2017-INV-0034, Disclosure date: 23/03/2017, record number: 2017033088953.