C1 Inhibits Liquid-Liquid Phase Separation and Oligomerization of Tau and Protects Neuroblastoma Cells against Toxic Tau Oligomers

Pradhan, A and Mishra, S and Surolia, A and Panda, D (2021) C1 Inhibits Liquid-Liquid Phase Separation and Oligomerization of Tau and Protects Neuroblastoma Cells against Toxic Tau Oligomers. In: ACS Chemical Neuroscience, 12 (11). pp. 1989-2002.

PDF acs_che-neu_12-11_1989-2002_2021.pdf - Published Version Restricted to Registered users only Download (12MB) | Request a copy

Abstract

The pathological aggregation of tau is one of the major contributing factors for several neurodegenerative tauopathies, including Alzheimer's disease. Here, we report that C1, a synthetic derivative of curcumin, strongly inhibited both the aggregation and filament formation of purified tau and protected neuroblastoma cells from the deleterious effects of the tau oligomers. Using confocal microscopy, C1 was found to reduce both the size and number of the tau droplets and increased the critical concentration of tau required for the droplet formation in vitro indicating that C1 suppressed the liquid-liquid phase separation of tau. C1 inhibited the aggregation of tau with a half-maximal inhibitory concentration of 1.5 ± 0.1 μM. An analysis of the aggregation kinetics data indicated that C1 strongly reduced the initial rate of the aggregation of tau. A dot blot analysis using tau-oligomer-specific antibody indicated that C1 inhibited the oligomerization of tau. Furthermore, dynamic light scattering experiments suggested that C1 strongly reduced the mean diameter of the tau oligomers. Atomic force microscopy experiments showed that C1 treatment reduced both the size and number of tau oligomers, suppressed the transition of tau oligomers into filaments, and also disintegrated preformed tau filaments. Also, the binding interaction of C1 with tau was monitored using absorbance and fluorescence spectroscopy. C1 bound to Y310W-tau with a dissociation constant of 2.0 ± 0.5 μM. The findings suggested that C1 is a potent inhibitor of tau aggregation and provided insights into the inhibitory mechanism of C1 on the oligomerization and fibril formation of tau. © 2021 American Chemical Society.

Item Type:	Journal Article
Publication:	ACS Chemical Neuroscience
Publisher:	American Chemical Society
Additional Information:	The copyright for this article belongs to American Chemical Society.
Keywords:	curcumin; tau protein, Alzheimer disease; human; neuroblastoma; tauopathy, Alzheimer Disease; Curcumin; Humans; Neuroblastoma; tau Proteins; Tauopathies
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	24 Feb 2023 04:51
Last Modified:	24 Feb 2023 04:51
URI:	https://eprints.iisc.ac.in/id/eprint/80441

Actions (login required)

View Item