Structure-Activity Relationship of Carbon Nitride Dots in Inhibiting Tau Aggregation

Area of Science:

• Biochemistry
• Materials Science
• Neuroscience

Background:

• Microtubule-associated protein tau (MAPT) aggregation is a key target for Alzheimer's disease (AD) therapy.
• Anti-amyloid drug trials have faced numerous failures, increasing focus on alternative therapeutic targets like MAPT.

Purpose of the Study:

• To investigate the structure-dependent inhibition of MAPT aggregation by carbon nitride dots (CNDs).
• To elucidate the structure-activity relationship of CNDs in the context of AD pathology.

Main Methods:

• Separation of CNDs into five fractions using column chromatography.
• Characterization of CND fractions using multiple spectroscopy methods.
• Assessment of MAPT aggregation inhibition capacity and validation via molecular dynamics simulations.
• Evaluation of CNDs' blood-brain barrier (BBB) penetration using a zebrafish model.

Main Results:

• Five CND fractions with varying polarity and surface hydrophilic groups were obtained.
• MAPT aggregation inhibition capacity decreased with increasing CND polarity, suggesting hydrophobic interactions.
• CNDs demonstrated passive diffusion across the zebrafish BBB.
• CNDs were found to inhibit reactive oxygen species generation.

Conclusions:

• CNDs show potential as an AD therapeutic by inhibiting MAPT aggregation and reducing oxidative stress.
• The polarity and hydrophobic interactions of CNDs are critical factors for their efficacy in inhibiting MAPT aggregation.
• CNDs possess the ability to cross the blood-brain barrier, a crucial property for CNS-acting drugs.