Clearance of Senescent Oligodendrocyte Cells as a Treatment for Alzheimer's Disease

The accumulation of lingering senescent cells is one of the root causes of aging. These cells secrete signal molecules that rouse the immune system to a state of chronic inflammation, resulting in disarray of tissue function and the progression of age-related disease. Recent studies in mouse models of Alzheimer's disease have shown that senescent microglia and astrocytes are important in the generation of neuroinflammation and tau pathology in this condition. The use of senolytics to remove these cells results in a significant reduction in pathology.

Here, researchers provide further evidence to show that accumulation of various types of senescent cells - and the inflammation that they generate - is likely a vital part of the bridge between early amyloid-β aggregation and later tau aggregation in Alzheimer's disease. Decades of slow amyloid-β aggregation may act as the foundation of the far more serious later stages of the condition in large part because this process provokes greater levels of lingering cellular senescence than would otherwise occur.

The most common cause of age-related dementia, Alzheimer's disease is marked by the aggregation of amyloid proteins, which can kill off surrounding neurons. The areas of amyloid accumulation and associated nerve cell death, called plaques, are a hallmark of the disease. Researchers found that a specific brain cell type, called oligodendrocyte progenitor cells, appears in high numbers near plaques. In a healthy brain, oligodendrocyte progenitor cells develop into cells that support nerve cells, wrapping them in a protective layer that heals injury and removes waste. The environment created by the amyloid proteins causes these progenitors to stop dividing and conducting their normal functions. In diseases such as Alzheimer's, the oligodendrocytes instead send out inflammatory signals that contribute more damage to the surrounding brain tissue. "We believe the amyloid is damaging the neurons, and although the oligodendrocytes move in to repair them, for some reason the amyloid causes them to senesce rather than complete their job."

The researchers suspected that if they could selectively remove malfunctioning senescent oligodendrocyte progenitor cells, they could slow Alzheimer's disease progression. The researchers tested the concept in mice that were genetically engineered to have some of the characteristics of Alzheimer's disease, such as aggregated amyloid plaques. To remove the senescent cells, the researchers devised a treatment with a mixture of two FDA-approved drugs: dasatinib and quercetin. Dasatinib was originally developed as an anti-cancer drug, and quercetin is a compound found in many fruits and vegetables. The drug combination was proven as an effective way to eliminate senescent cells in previous studies of other diseases. The researchers administered the drugs to groups of the Alzheimer's mice for nine days, then examined sections of the mice's brains for signs of damage and the presence of senescent oligodendrocyte progenitor cells.

They report that the mice treated with the drugs had approximately the same amount of amyloid plaques as mice that received no treatment. However, the researchers say they found that the number of senescent cells present around these plaques was reduced by more than 90 percent in mice treated with the drug combination. They also found that the drugs caused the senescent oligodendrocyte progenitor cells to die off. Together, these results show that the dasatinib and quercetin treatment effectively eliminated senescent oligodendrocyte progenitor cells.

The researchers next tested whether the physical benefits of the dasatinib and quercetin treatment could protect the mice against the cognitive decline associated with Alzheimer's disease. To do that, the researchers fed the genetically engineered mice the dasatinib and quercetin drug combination once weekly for 11 weeks, beginning when the mice were 3 1/2 months old. The researchers periodically evaluated the mice's cognitive function by observing how they navigated mazes. They found that after 11 weeks, control mice who got no drug treatment took twice as long to solve the maze as their counterparts treated with dasatinib and quercetin. After 11 weeks, the researchers again analyzed the brains of the mice and found 50 percent less inflammation in mice treated with dasatinib and quercetin, compared with nontreated mice. The researchers say these results show that eliminating senescent cells from the brains of affected mice protected cognitive function and reduced inflammation linked to Alzheimer's disease-like plaques.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/restoring-brain-function-in-mice-with-symptoms-of-alzheimers-disease

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