Rare population of toxic senescent cells in brain could be target for treatment of Alzheimer’s disease

For the first time, scientists have identified a rare population of potentially toxic senescent cells in the human brain that could serve as a target for a new treatment for Alzheimer’s disease.

The study, published in the December 10 edition of the journal Nature Aging, was led by Miranda Orr, Ph.D., assistant professor of gerontology and geriatric medicine at the Wake Forest School of Medicine and health research scientist. at WG Hefner VA Medical Center, and Habil Zare, Ph.D., assistant professor of cellular systems and anatomy, at the University of Texas Health San Antonio. The study was funded by the US Department of Veterans Affairs and the National Institute on Aging.

Senescent cells are old, diseased cells that cannot repair themselves properly and do not die when they should. Instead, they work abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues all over the body, contributing to the aging process, neurocognitive decline, and cancer.

Research by Orr in 2018 found that senescent cells accumulate in mouse models of Alzheimer’s disease where they contribute to brain cell loss, inflammation and memory impairment. When the researchers used therapy to remove senescent cells, they stopped disease progression and cell death.

However, until now, we didn’t know how much senescent cells accumulate in the human brain, and what they actually look like. It was a bit like looking for the proverbial needle in a haystack, except we didn’t know what the needle looked like. “

Miranda Orr, Ph.D., Assistant Professor of Gerontology and Geriatric Medicine, Wake Forest School of Medicine

Using sophisticated statistical analyzes, the research team was able to assess large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brain of people who died from Alzheimer’s disease. The researchers’ plan was to determine first if there were any senescent cells, then how many and what types of cells they were. They succeeded.

The team found that around 2% of brain cells were senescent and also identified the cell type and characteristics.

The results of the study indicated that senescent cells were neurons, which are the fundamental units of the brain that process information and are the workhorses of memory. These are also the primary cells that are lost in Alzheimer’s disease.

Next, Orr’s team set out to determine whether senescent neurons were entangled – abnormal buildups of a protein called tau that can build up inside neurons in Alzheimer’s disease. These tangles are closely related to the severity of the disease, which means that the more tangles people have in their brains, the worse their memory is, Orr said.

The researchers found that the senescent neurons were not only entangled, but overlapped to the point that it was difficult to tell them apart.

Finally, the team validated the results by examining a different cohort of post-mortem brain tissue samples from people with Alzheimer’s disease.

“Now that we’ve identified these cells in the brain, we’ve opened the door to a lot of possibilities, including treatment options for people with Alzheimer’s disease,” Orr said.

Orr is launching a $ 3 million Phase 2 clinical trial funded by the Alzheimer’s Drug Discovery Foundation (ADDF) to test the effects of removing senescent cells in older people with mild cognitive impairment or early stage of Alzheimer’s disease. The intervention, which was discovered by Orr’s collaborators at the Mayo Clinic, involves administering a drug approved by the U.S. Food and Drug Administration designed to kill cancer cells in combination with a flavonoid, an antioxidant of ‘vegetable origin.

The therapy has worked well in mouse models of Alzheimer’s disease and has been shown to be safe in humans with other conditions, as previously reported by a team involving the Wake Forest School of Medicine, University of the Texas Health in San Antonio and the Mayo Clinic. The three sites will again collaborate in the ADDF-funded clinical trial, Orr said.

“Dr. Orr’s groundbreaking research stands out as an exciting new way to target one of the many underlying factors that contribute to Alzheimer’s disease,” said Howard Fillit, MD, founding executive director and scientific director of the ‘Alzheimer’s Drug Discovery Foundation.

“Dr Orr and his team are leading the way in senolytic research for Alzheimer’s disease, opening a new target for potential treatments. This is particularly exciting for the field because we now know that we will need drugs that work. against the many underlying biological processes that go wrong with age – like the accumulation of toxic senescent cells – that contribute to Alzheimer’s disease. “


Journal reference:

Dehkordi, SK, et al. (2021) Profiling of senescent cells in the human brain reveals neurons with CDKN2D / p19 and tau neuropathology. Natural aging. doi.org/10.1038/s43587-021-00142-3.

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