'Zombie' Cells a New Treatment Target for Alzheimer's?

Pauline Anderson

December 10, 2021

Scientists have identified a potential new target for Alzheimer's disease (AD) treatment.

Investigators led by Miranda E. Orr, PhD, assistant professor of gerontology and geriatric medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, have detected a rare population of potentially senescent cells, also known as "zombie cells," in the brains of patients with AD.

The study adds to the growing knowledge about how the biology of aging contributes to AD. This new information may help researchers find treatments that prevent cell senescence or remove senescent cells from the brain to slow or stop the progression of AD and/or improve related symptoms.

The pursuit of therapies that eliminate senescent cells is known as "senolytic" research.

The research was published online December 10 in Nature Aging.

Autopsy Data

There is mounting interest among AD researchers in "cell senescence," which refers to arrested cell division.

As individuals age, continued exposure to various stressors leads to an increase in the number of cells that become senescent. These cells may become resistant to cell death, change shape and size, and secrete inflammatory molecules.

In animal models, senescent cells contribute to pathology and brain dysfunction. Animal research also shows that depletion of senescent cells delays the onset of age-related diseases.

However, the sparse distribution and heterogeneous phenotype of these cells have presented challenges for detecting them in human tissue.

Now, using large, diverse populations of postmortem human brain tissue from patients with various levels of AD pathology, the researchers have developed, tested, and validated a technique involving "eigengenes" to identify these rare cells.

Eigengenes are useful when no single gene reliably captures a phenotype such as senescence, the investigators say. Each of their eigengenes detected about 2% senescent cells from a population of approximately 140,000 single nuclei derived from 76 postmortem human brains.

"Exciting New Target"

Commenting on the study, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation (ADDF), described the research as innovative and that it "stands out as an exciting new way to target one of the many underlying factors that contribute to Alzheimer's disease."

"Dr Orr and her team are paving the way in senolytics research for Alzheimer's disease, opening up a new target for potential treatments," Fillit said in a release.

"This is especially exciting for the field as we now know we will need drugs that work against the many underlying biological processes that go wrong as we age ― like the build-up of toxic senescent cells ― that contribute to Alzheimer's disease," he added.

The ADDF is providing support for a phase 2 clinical trial that will build on this research to test the effects of clearing these senescent cells in older adults with mild cognitive impairment or early-stage AD.

With nearly 6 million Americans living with AD, there's a growing need to identify new therapies that address senescent cells and other novel targets, such as brain inflammation and vascular dysfunction, that can be used in combination to improve the outlook for people with AD, Fillit noted.

The study was supported by the NIH/NIA, the Cure Alzheimer's Fund, and Veterans Affairs.

Nat Aging. Published December 10, 2021. Abstract

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