Restoring brain function in mice with symptoms of Alzheimer’s disease

Summary: Senolytic drugs administered to mice reduced senescent cells around amyloid plaques by more than 90% and decreased neuroinflammation by 50%. Mice treated with the drug combination also showed improvements in spatial memory, compared to other Alzheimer’s model mice who received no treatment. The findings could have positive implications for the treatment of Alzheimer’s disease in people with the condition.

Source: Johns Hopkins Medicine

A study in mice shows that selectively removing cells that are no longer dividing from the brains of mice with a form of Alzheimer’s disease can reduce brain damage and inflammation, and slow the pace of cognitive decline. These findings, say researchers, add to evidence that such senescent cells contribute to the damage caused by Alzheimer’s disease in people.

“Our results show that eliminating these cells may be a viable route to treat Alzheimer’s disease in humans,” says Mark Mattson, Ph.D., senior investigator in the Laboratory of Neurosciences at the National Institute on Aging and professor of neuroscience at the Johns Hopkins University School of Medicine.

A report on the work was published April 1 in Nature Neuroscience.

Alzheimer’s disease is an age-related degenerative disease of the brain that affects an estimated 5.8 million Americans. The most common cause of age-related dementia, the disorder 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. To date there are no known successful treatments for the disease, and as these plaques begin to form, patients experience progressive memory loss, learning impairment and, in later stages, delusions and paranoia.

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,” says Mattson.

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 U.S. Food and Drug Administration-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.

Cellular senescence is an emerging area of interest in studies of age-related disease such as Alzheimer’s, says Mattson. It has been most extensively studied in peripheral tissues, such as skin, where older cells are rapidly replaced by new ones. In these tissues, senescent cells accumulate as a normal part of aging, causing some of the well-known signs of aging skin, including wrinkles, stiffness and fragility.

This is a drawing of neurons

Researchers found that a specific brain cell type, called oligodendrocyte progenitor cells, appears in high numbers near plaques. The image is adapted from the Johns Hopkins Medicine news release.

Mattson cautions that mice genetically engineered to have Alzheimer’s symptoms and characteristics do not directly mimic the biological processes of the human condition. For example, mouse brain cells do not die as amyloid plaques form, while human brain cells do.

Other researchers involved in this study include Peisu Zhang, Yuki Kishimoto, Ioannis Grammatikakis, Kamalvishnu Gottimukkala, Roy Cutler, Shiliang Zhang, Kotb Abdelmohsen, Vilhelm Bohr and Myriam Gorospe of the National Institute on Aging Intramural Research Program; and Jyoti Misra Sen of the National Institutes on Aging Intramural Research Program and the Johns Hopkins University School of Medicine.

Funding: This research was supported by the Intramural Research Programs of the National Institute on Aging and the National Institute on Drug Abuse, and by a National Institute on Aging grant supporting the University of Kentucky Alzheimer’s Disease Research Center (P30-AG0-28383).

The authors declare no competing interests.

About this neuroscience research article

Source:
Johns Hopkins Medicine
Media Contacts:
Rachel Butch – Johns Hopkins Medicine
Image Source:
The image is adapted from the Johns Hopkins Medicine news release.

Original Research: Closed access
“Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Peisu Zhang, Yuki Kishimoto, Ioannis Grammatikakis, Kamalvishnu Gottimukkala, Roy G. Cutler, Shiliang Zhang, Kotb Abdelmohsen, Vilhelm A. Bohr, Jyoti Misra Sen, Myriam Gorospe & Mark P. Mattson. Nature Neuroscience 22, pages719–728 (2019). doi:10.1038/s41593-019-0372-9

Abstract

Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model

Neuritic plaques, a pathological hallmark in Alzheimer’s disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.

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