Recognizing that Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world, scientists have sought therapeutic interventions capable of curbing it. Although cognitive decline and brain atrophy correlate with tau fibril formation in AD, finding effective therapies that enter the brain, penetrate neurons and break them down remains challenging. The green tea molecule, EGCG, is known to break down tau fibers – multilayered filaments that form tangles that attack neurons – causing their death.
Biochemists at UCLA (USA) have described how this compound breaks down tau fibers layer by layer. They also discovered other molecules that likely work similarly and would be better potential drug candidates. The finding
opens new possibilities to combat Alzheimer’s, Parkinson’s, and other related diseases.
Thousands of J-shaped layers of tau molecules together make up the type of amyloid fibrils known as tangles, first observed a century ago by Alois Alzheimer in the postmortem brain of a dementia patient. These fibers grow and spread throughout the brain, killing neurons and inducing brain atrophy. EGCG has been studied a lot, but it has never worked as an Alzheimer’s drug because its ability to dismantle fibers works best in water and doesn’t easily enter cells or the brain. In addition, as soon as it enters the bloodstream, it binds to many proteins, which weakens its effectiveness.
To investigate the mechanism, the researchers extracted tau tangles from the brain postmortem and incubated them for various periods with EGCG. Half of the fibers had disappeared at three hours, and those remaining were partially degraded. After 24 hours, all the threads had disappeared.
Fibrils in the middle of the induced degradation were frozen, and images of these samples showed the compound breaking the fibrils into seemingly harmless pieces.
Kevin Murray, who was then a doctoral student at UCLA and now works in the department of neurology at Brown University, identified specific places, called pharmacophores, on the tau fiber to which the EGCG molecules attached. Next, he ran simulations of a library of 60,000 brain- and nervous-system-friendly small molecules with the potential to bind to the same sites. Experiments with the main candidate molecules identified from the computational screening allowed us to remember about half a dozen.
Some of these major compounds, most notably molecules called CNS-11 and CNS-17, also prevented the fibers from spreading from cell to cell. The authors believe that these molecules are drug candidates that could be developed to treat Alzheimer’s disease.