Senescent cells accumulate with age throughout the body, and disrupt tissue structure and function via their inflammatory sections. Work on senolytic drugs capable of clearing senescent cells from aged tissues has in recent years pointed to cellular senescence in the supporting glial cells of the brain as an important mechanism in neurodegenerative conditions. Clearing a sizable fraction of senescent microglia and astrocytes in mouse models of tauopathy reduces harmful tau aggregation and neuroinflammation, a promising result. The senolytic treatment used, the combination of dasatinib and quercetin, both of which pass the blood-brain barrier, will soon be used in a human trial with Alzheimer's patients. I've suggested in the past that it seems plausible at this point that the best Alzheimer's therapy of the next decade or two will be some form of senolytic treatment.
Today's popular science coverage discusses work that points to a bidirectional relationship between pathological tau aggregation, characteristic of the late stage of Alzheimer's disease, and the accumulation of senescent glial cells in the brain. It isn't just that senescent cells provoke an inflammatory state that encourages tau aggregation, but also that tau aggregation leads to more cells becoming senescent. There is considerable debate over how exactly Alzheimer's emerges in its early stages, but researchers are more agreed that later stages of the condition have the look of a runaway feedback loop between cellular senescence and other forms of pathology in the brain, such as tau aggregation. Senolytic drugs may well turn out to be a good way to interfere in that process in humans; we'll know whether or not this is the case a few years from now.
Scientists had previously reported that removing senescent glia from mouse models of tauopathy protected them from neurodegeneration. But what made those glia senescent to begin with? Researchers now claim it was tau. They detail how tau oligomers inflamed astrocytes in culture, prompting them to expel a protein called high mobility group box 1 (HMGB1). HMGB1 then led adjacent cells down the path to senescence. Inhibiting HMGB1 release prevented this culture of corruption and, in mouse models of tauopathy, it not only reduced senescent astrocytes but also the amount of tau oligomers and tangles. The animals' short-term memory also improved.
HMGB1 is a nuclear protein involved in DNA replication and repair. Its appearance in the cytosol signals cellular senescence. Released by glia, it can activate nearby cells to crank out inflammatory cytokines, ultimately damaging tissue through a process called senescence-associated inflammation. Researchers previously found HMGB1 in the cytosol of astrocytes that were surrounded by tau oligomers in Alzheimer's disease (AD) and frontotemporal dementia (FTD) postmortem tissue. Did HMGB1 relocalization within astrocytes indeed indicate senescence and contribute to tau pathology?
To find out, researchers examined frontal cortex tissue taken postmortem from eight people who had had AD, six people who had FTD, and eight age-matched controls. In the AD and FTD samples, 75 percent of astrocytes were senescent and had oligomers of tau within or nearby. Researchers found HMGB1 in their cytoplasm. Did the oligomers cause senescence? To find out, the researchers cultured astrocytes from healthy wild-type mice and treated them with oligomers made from recombinant human tau. The astrocytes took up the oligomers. Eleven days later, HMGB1 had turned up in the cytoplasm, ultimately escaping into the culture medium. Seventy percent of the tau-exposed astrocytes also expressed p16 and had high β-gal activity.
Would inhibiting HMBG1 release from cells have any benefit in the brain? To find out, researchers treated 12-month-old hTau mice with ethyl pyruvate (EP) and glycyrrhizic acid (GA), two inhibitors of HMGB1 release, three times a week for eight weeks. These mice express six isoforms of human tau and have significant tangles, gliosis, neurodegeneration, and cognitive problems by 1 year of age. Compared to control mice, inhibitor-treated mice were more curious about new objects and environments, hinting that their short-term memory had improved. In keeping with this, the treated mice had fewer tangles and less phosphorylated tau in the hippocampus.