Tau Tangles Cleared by Senolytic Drugs in Alzheimer’s Mice

Tangles of tau protein in the brain constitute a hallmark of Alzheimer’s disease, but exactly how these tangles exert their toxic effects remains poorly understood. In hopes of untangling tau’s mysteries, scientists based at the UT Health San Antonio delved into postmortem brain tissue from Alzheimer’s patients and generated transcriptomic profiles. These profiles revealed expression profiles consistent with cellular senescence, a kind of stressed state that allows cells to survive, albeit in a zombie-like and proinflammatory state.

Using mouse models of Alzheimer’s disease, the UT Health scientists further explored the possibility that tau and senescence are linked. The scientists found that senolytic drugs, which target and kill senescent cells, helped clear tau protein tangles. Moreover, the drugs slowed neuronal loss, suggesting that the curbing of cell senescence could be a way to treat Alzheimer’s and other neurodegenerative conditions.

Details of the new work appeared  in the journal Aging Cell, in an article entitled, “Tau protein aggregation is associated with cellular senescence in the brain.” The article describes how the tau-senescence link emerged from transcriptomic analyses of neurons microdissected from postmortem brain tissue of Alzheimer’s patients, neurons afflicted with tau-containing neurofibrillary tangles (NFTs).

“Transcriptomic analyses revealed an expression profile consistent with cellular senescence,” the article’s authors indicated. “This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction.”

The article also describes how the researchers used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer's mice. The drugs are dasatinib, a chemotherapy medication that is FDA-approved to treat leukemia, and quercetin, a natural flavonoid compound found in fruits, vegetables, and some beverages such as tea.

“Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells,” the article noted. “Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement.”

“The mice were 20 months old and had advanced brain disease when we started the therapy,” says study senior author Miranda E. Orr, Ph.D., a pharmacologist at UT Health San Antonio. “After clearing the senescent cells, we saw improvements in brain structure and function. “The treatment seems to have stopped the disease in its tracks.”

“The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease,” adds Nicolas Musi, M.D., the study's first author, and is a professor of medicine and director of the Sam and Ann Barshop Institute at UT Health San Antonio.

Dasatinib is an oral medication. The mice were treated with the combination every other week. “So, in the three months of treatment, they only received the drug six times,” Dr. Orr notes. “The drug goes in, does its job and is cleared. Senescent cells come back with time, but we expect that it would be possible to take the drug again and be cleared out again. That's a huge benefit—it wouldn't be a drug that people would have to take every day.”

Dosage and frequency in humans would need to be determined in clinical trials, Dr. Orr indicated.

Next, the researchers will study whether cell senescence is present in traumatic brain injury, which is a brain injury that develops tau protein accumulation and is a significant cause of disability in both military and nonmilitary settings.