Research

 

• Liquid-Liquid Phase Separation (LLPS) of Tau:​

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        Liquid-liquid phase separation (LLPS) of biological polymers (protein and RNA) has emerged as a critical phenomenon in the formation of intracellular ‘membrane-less’ organelles. The project has been designed to develop mechanistic detail involved in the formation of tau condensates via LLPS involved in Alzheimer's disease and other tauopathies. Also, The role of several biophysical factors (such as pH, temperature, crowding agents, and several low-range forces) associated with LLPS constitutes a major part of the project.

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• Biophysical Mechanism of Amyloid Aggregation and Inhibition:

 

     This project was aimed to explore the chemistry of low molecular weight (LMW) amyloid oligomers. The most toxic LMW oligomer (tetramer) has been isolated and their biophysical properties have been explored. A novel engineered gold nanoparticle functionalized with N-methyl D-aspartic acid has been developed and shown to regulate the nucleation pathway of amyloid tetramers and mitigate their toxicity in vitro. (Role: First Author, status: Published, ACS Appl. Bio Mater. 2019, 2, 2137–2142).

 

     In spite of having excellent anti-Alzheimer properties, such nanoparticles are nonfluorescent in nature which limits in vivo applications. Hence, a conjugated polymeric template (backbone polyfluorene) functionalized with Isatin moiety was developed. The template was observed to block pathological aggregation of amyloid- β by forming a nontoxic amyloid-polymer co-aggregates and disaggregates preformed mature amyloid aggregates present in human cerebrospinal fluid. (Role: First Author, status: Published, ACS Appl. Bio Mater. 2019, 2, 5306–5312).

 

       However, the aforementioned polymer remains unable to permeate through the blood-brain barrier(BBB). To address the issue, the receptor group was changed to Benzimidazole. Newly developed benzimidazole functionalized polyfluorene was found to form nanodot in aqueous media and permeates through BBB and protect neuro cells from amyloid-mediated neurotoxicity elucidated in a wild-type mouse model. The mechanism of neuroprotection was further explored using the SH-SY-5Y neuroblastoma cell line. It was found that amyloid oligomers kill neuro cells through ROS-mediated mitochondrial dysfunction. However, the polymeric probe functions like a chaperone and selectively binds with the amyloidogenic domain to block the process of oligomerization which further inhibits a biochemical pathway that results in ROS-mediated mitochondrial dysfunction. (Role: First Author, status: Published, ACS Chem. Neurosci. 2020, 11, 3277–3287).

 

      In addition to this, I have also developed a small molecule-based therapeutic probe that electrostatically interacts with amyloid-beta. Simulation and NMR technique was used to explore the detailed interaction between the molecule and amyloid β. The probe actually inhibits a chain of neurochemical processes that leads to caspase-mediated neuronal damage. The molecule is also permeable to BBB and reduces internal hemorrhage induced by amyloid oligomers elucidated in a wild-type mouse model. (Role: First Author, status: Submitted).

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• Molecular Chaperones to Target Intrinsically Disordered Protein:

 

        I am presently working to reduce the aggregation propensity of alpha-synuclein. I have developed a novel polymer-based synthetic molecular chaperone that binds with alpha-synuclein and thereby stops it from forming toxic aggregates. The polymer-peptide interaction is found to be exothermic in nature which results in suppression in the overall entropy of the system. The decrease in entropy was observed in a dose-dependent manner and may dramatically affect their toxicity. (Role: First Author, status: work under process).

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• Development of Novel Electrochemical Device for Rapid Diagnosis of Alzheimer's Disease in Early Stage:

 

       Low molecular weight amyloid oligomers have been universally accepted as an early-stage biomarker for Alzheimer’s disease. A two-terminal electrochemical device has been fabricated to detect the presence of LMW amyloid oligomers in human cerebrospinal fluid (HCSF). The device has been intensively tested against a library of HCSF samples (from a wide range of age groups) collected from nearby city general hospitals. The device produces a unique signal in the presence of LMW amyloid oligomers. (Role: First Author, status: Patent file under process).

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