Researchers have discovered how a molecule found in green tea breaks apart tangles of the protein tau, a hallmark of Alzheimer’s disease. Based on this finding, the team identified other molecules that can also untangle tau and may be better drug candidates than the green tea molecule. Results from the NIA-funded study, published in Nature Communications, suggest that this approach may one day provide an effective strategy for treating Alzheimer’s.
In Alzheimer’s, tau abnormally sticks together in fibrous tangles that spread between brain cells, leading to cell death. The molecule epigallocatechin gallate (EGCG) — the one found in green tea — is known to untangle these tau fibers. However, EGCG is not on its own an effective Alzheimer’s treatment because it cannot easily penetrate the brain and binds to many proteins other than tau, weakening its effect. Therefore, researchers wanted to find molecules that replicate the effects of EGCG but have better drug properties for treating Alzheimer’s.
In this study, a team led by investigators at the University of California, Los Angeles, isolated tau tangles from postmortem brain tissue donated by people who had Alzheimer’s. The tangles were treated with EGCG and flash frozen. Images of the EGCG and tau fiber complexes were captured with a technique called cryogenic electron microscopy.
These EGCG-tau fiber images helped reveal how EGCG attaches to and dismantles the tau fibers. According to the team’s model, EGCG binds to clefts, or openings, along each layer of the fibers, destabilizing the layers and slowly prying the fibers apart.
Using computer simulations, the researchers identified other molecules likely to work in a similar way as EGCG but that may be able to enter the brain more easily. They tested these other molecules in a cell model for tau tangle formation and additionally on tau tangles isolated from brain samples donated by Alzheimer’s patients after death. In both setups, several of the molecules untangled tau fibers. Although researchers caution that more work is needed, the experiments indicated that certain molecules also prevented the untangled tau from spreading and forming new tangles.
Overall, the findings suggest that these newly discovered molecules that can penetrate the brain and dismantle tau tangles may be a promising strategy for treating Alzheimer’s. Future research into these molecules may help uncover more about their therapeutic potential.
This research was supported in part by NIA grants R01AG070895 and R01AG048120.
Reference: Seidler PM, et al. Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro. Nature Communications. 2022;13(1):5451. doi: 10.1038/s41467-022-32951-4.