Emerging evidence suggests it may be possible to treat Alzheimer’s disease by targeting therapy at senescent cells in the brain.
On Dec. 10, in the journal Nature Aging, a team from The University of Texas Health Science Center at San Antonio and Wake Forest School of Medicine reported the first method, based on computational analysis, to objectively identify and quantify these toxic cells. In addition to having value in monitoring the effectiveness of senescent cell therapy, this method could prove to be a highly effective diagnostic tool in detecting Alzheimer’s.
The study was led by Habil Zare, Ph.D., assistant professor of cell systems and anatomy at UT Health Science Center San Antonio, and Miranda Orr, Ph.D., assistant professor of gerontology and geriatric medicine at Wake Forest School of Medicine and research health scientist at the W.G. Hefner VA Medical Center. Dr. Zare is a researcher with the health science center’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.
The Biggs Institute, the Sam and Ann Barshop Institute for Longevity and Aging Studies and the Alzheimer’s Disease Research Center (ADRC), a National Institute on Aging Center of Excellence that is a collaboration of UT Health Science Center San Antonio and The University of Texas Rio Grande Valley, were key contributors to the study. The research was funded by the U.S. Department of Veterans Affairs and National Institute on Aging.
Obsolete cells that don’t die
If a cell is old, stressed or damaged by insults such as radiation, it may enter a state in which it can no longer divide or function properly. This is senescence. These cells cannot properly repair themselves and don’t die off when they should. They have been called “zombie cells” for this reason. Instead, senescent cells function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body, contributing to the aging process, cognitive decline and cancer.
Research conducted by Dr. Orr in San Antonio in 2018 found that senescent cells accumulated in mouse models of Alzheimer’s disease. The cells contributed to brain cell loss, inflammation and memory impairment. When the researchers used a therapy to clear the senescent cells, they halted disease progression and cell death in mice.
Revealing a senescence signature
However, it hasn’t been known to what extent the non-dividing zombie cells accumulate in the brain or what they look like.
“There is a debate in the field on which senescence marker to use, and, in practice, senescence has no single marker because it is presented differently in various cell types, conditions and stages,” Dr. Zare said. “When we started the study, we didn’t know which marker to use for senescent brain cells. Starting with a collection of candidate markers, we analyzed them with our unbiased computational approach. This identified a signature for senescence that is a combination of several of the markers.”
Having a signature for senescence will be important clinically for baseline measurements at the time patients are first seen by a neurologist and then to track the impact of medication. Identifying populations of senescent cells is also important to understand how and why cells become senescent.
Using statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer’s disease. The researchers looked for the presence of senescent cells and then their quantity and types.
Neurons lost in Alzheimer’s
The team found that approximately 2% of the brain cells were senescent. The researchers also identified the type of cell and the characteristic features. The study findings indicated that the senescent cells were mostly neurons, which are central nervous system cells in the brain that are lost in Alzheimer’s disease.
“Interestingly, in this study we showed that senescent neurons significantly overlap with neurofibrillary tangles, which are pathological hallmarks of Alzheimer’s disease,” Dr. Zare said.
Finally, Jamie Walker, MD, PhD, the neuropathologist of the team, led validation of the findings by examining a different set of postmortem brain tissue samples from people with Alzheimer’s. Specimens were provided from the Glenn Biggs Institute Brain Bank.
“Now that we have identified these cells in the brain, we have opened the door to many possibilities, including treatment options for people with Alzheimer’s,” Dr. Orr said in a Wake Forest press release.
Dr. Orr is launching a $3 million, Phase 2 clinical trial funded by the Alzheimer’s Drug Discovery Foundation (ADDF) to test the effects of clearing senescent cells in older adults with mild cognitive impairment or early stage Alzheimer’s. The intervention, which was discovered by Dr. Orr’s collaborators at the Mayo Clinic, consists of administering a repurposed U.S. Food and Drug Administration-approved drug designed to clear cancer cells in combination with a flavonoid, a plant-derived antioxidant.
The therapy worked well in Alzheimer’s disease mouse models and has proven safe in humans with other conditions, as previously reported by a team involving Wake Forest School of Medicine, UT Health Science Center San Antonio and the Mayo Clinic. The three sites will again collaborate on the ADDF-funded clinical trial, Dr. Orr said.
The study was supported by the National Institutes of Health/National Institute on Aging R01AG068293, R01AG057896, U01AG046170, RF1AG057440, R01AG057907, K99AG061259; P30AG062421; RF1AG051485, R21AG059176, and RF1AG059082 and T32AG021890; and Cure Alzheimer’s Fund; and Veterans Affairs K2BX003804.
Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology
Shiva Kazempour Dehkordi, Jamie Walker, Eric Sah, Emma Bennett, Farzaneh Atrian, Bess Frost, Benjamin Woost, Rachel E. Bennett, Timothy C. Orr, Yingyue Zhou, Prabhakar S. Andhey, Marco Colonna, Peter H. Sudmant, Peng Xu, Minghui Wang, Bin Zhang, Habil Zare and Miranda E. Orr
First published: Dec. 10, 2021, Nature Aging