Inhibition and Disassembly of Tau Aggregates by Engineered Graphene Quantum Dots

Abstract

Tauopathies are a class of neurodegenerative diseases resulting in cognitive dysfunction, executive dysfunction, and motor disturbance. The primary pathological feature of tauopathies is the presence of neurofibrillary tangles in the brain composed of tau protein aggregates. Although numerous small molecules are known to inhibit tau aggregation, it is still challenging to use them for therapeutic applications due to their limitations in specific targeting and the blood-brain barrier (BBB) penetration. Graphene quantum dots (GQDs), one of graphene nanoparticles, can penetrate the BBB and are amenable to functionalization for targeted delivery. Moreover, these nanoscale biomimetic particles can self-assemble or assemble with various biomolecules including proteins. In this paper, for the first time, we showed that GQDs interacted with tau proteins via electrostatic and {pi}-{pi} stacking interactions to inhibit the fibrillization of monomeric tau and to trigger the disaggregation of tau filaments. In vitro thioflavin T assays demonstrated that negatively charged GQDs with larger sizes inhibited tau aggregation more efficiently, while positively charged ones were more effective in the disassembly of tau fibrils. Moreover, GQDs blocked the seeding activity of tau fibrils in a cellular propagation assay. Overall, our studies indicate GQDs with engineered properties can efficiently inhibit and disassemble pathological aggregation of tau proteins, which supports their future developments as a potential treatment for tauopathies.