As a companion piece to recent research on immune dysfunction in the central nervous system as the bridge between early amyloid-β and later tau pathology in Alzheimer's disease, here is a another recent discussion of work demonstrating cellular senescence to arise from amyloid-β aggregation in the brain. In this view of Alzheimer's disease, the primary reason why amyloid-β plaques set the stage for the later, much more harmful phase of the condition, is that the plaques cause cells to become senescent. These cells secrete a mix of inflammatory signals, and the consequent neuroinflammation and dysfunction of immune cells spurs aggregation of tau into neurofibrillary tangles. That in turn causes cell death, synaptic destruction, dementia, and death.
Fortunately, these new discoveries strongly suggest that senolytic therapies that can bypass the blood-brain barrier should be effective in treating Alzheimer's disease. Quite effective in comparison to any existing therapy, at least, which is admittedly a low bar to pass at this point in time. Nonetheless, given the robust results produced by senolytics for all of the other most common inflammatory conditions of aging in animal studies, we might be optimistic. Recent demonstrations in mice have shown reversal of neuroinflammation and tau pathology via the use of senolytic drugs, reinforcing this hope. We shall see how this progresses in humans in the years ahead.
A new study adds evidence that Alzheimer's disease (AD) pathology makes nearby cells senescent. Scientists now report that in both people and animals, oligodendrocyte precursor cells (OPCs) surrounding amyloid-β (Aβ) plaques stop differentiating into myelin-repairing oligodendrocytes. Instead, they release inflammatory molecules into their environment and leave damaged axons bare of myelin. Drugs that clear senescent cells - known as senolytics - eliminated senescent OPCs and reduced neuroinflammation, microgliosis, and Aβ load in transgenic mouse models of AD, all the while improving their learning and memory. The results tap senolytic drugs as a potential therapy for Alzheimer's disease.
Senescent cells are proliferative cells that have stopped dividing with age, usually after a certain number of divisions. They remain metabolically active, however, releasing proinflammatory cytokines. Senescent cells have been found to contribute to peripheral disorders, including diabetes, cancer, and atherosclerosis. Scientists have started asking whether senescent cells accumulate in the brain. Researchers found that neurons containing tangles had entered a senescent state in both postmortem AD brain tissue and rTg4510 mice. They reported that tau pathology caused senescence of astrocytes and microglia in PS19 mice. Both sets of researchers found that clearing away the aged cells prevented or slowed neurodegeneration and cognitive deficits in mice.
Do Aβ plaques bring about senescence in the brain? In the current study, researchers examined human postmortem tissue. In samples of the inferior parietal cortices of eight AD patients, eight with mild cognitive impairment, and eight age-matched controls, they used antibodies to label Aβ plaques, microglia, astrocytes, and OPCs. OPCs occur throughout the brain - even in gray matter where there are fewer myelinated axons than in white matter - and they migrate to sites of neurodegeneration to repair myelin there. In AD patients, OPCs co-localized with markers of senescence, namely tumor-suppressor proteins p16 and p21, in 80 percent of the plaques. Astrocytes and microglia did not appear to be senescent.
What if the researchers cleared senescent OPCs from mouse brains? Zhang treated APPPS1 mice with two FDA-approved senolytic compounds. Dasatinib and quercetin (D+Q) eliminate senescent cells from tissues by transiently inhibiting tyrosine kinases that suppress apoptosis, thus killing only senescent cells. Because it takes time for healthy, dividing OPCs to become senescent, the drugs can be given intermittently. In this way, treating 5-month-old APPPS1 mice for nine days halved OPC senescence. Once-weekly treatments for 11 weeks beginning at 3.5 months old almost eliminated senescent OPCs in the hippocampi of APPPS1 mice. These animals better remembered which arm they had previously explored in a Y maze and where the hidden platform was in a water maze. D+Q treated mice accumulated about one-third the Aβ plaque load and half the level of inflammatory cytokines in the hippocampus and entorhinal cortex, as untreated controls.