Senescent cells function abnormally and release toxic substances that kill surrounding healthy cells and cause inflammation. They build up over time, contributing to the aging process, neurocognitive decline and cancer.
Earlier work by Dr. Miranda Orr of Wake Forest School of Medicine in Winston-Salem and colleagues found that senescent cells accumulated in mouse models of AD, and that the cells could be cleared, halting disease progression.
Now, in an upcoming phase 2 trial, the broad-spectrum tyrosine kinase inhibitor dasatinib, which is approved to treat leukemia, will be tested at a different dose and schedule to see if it can help clear the senescent cells, Dr. Orr told Reuters Health by email. The first study subject is scheduled to be screened at Wake Forest during Christmas week.
The team describes in Nature Aging the work that laid the groundwork for the trial. First, they developed a senescence eigengene approach to identify the senescent cells (which make up only about 2% of brain cells overall) within large, diverse populations of postmortem human brain cells from 76 people with various levels of AD.
They found that more than 97% of the senescent cells were excitatory neurons that overlapped with tau-containing NFTs.
Cyclin-dependent kinase inhibitor 2D (CDKN2D/p19) was implicated as the most significant contributor to the senescence eigengene. RNAscope and immunofluorescence confirmed that its expression was elevated in AD brain tissue; p19-expressing neurons had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons.
The team then validated the findings by examining a different cohort of postmortem brain tissue from people with AD.
Dr. Orr said, "We have several active areas of on-going investigation that span experiments aimed at understanding the role of p19 in senescence (i.e., what is causing its level to increase, at what age in the adult life does it first appear, is it important for senescence in other chronic diseases of the nervous system, etc.); understanding the link between tau pathology and senescence; developing methods to identify senescent cells in living humans, etc."
Dr. Markus Riessland, Assistant Professor, Empire Innovation Program (Aging Brain) in the Center for Nervous System Disorders at Stony Brook University in New York, commented on the study in an email to Reuters Health. "In my opinion, this approach is very promising and ready for phase 2 because the proposed drugs are FDA-approved. If senolytics treatment can remove senescent neurons from Alzheimer's patients' brains, it would potentially ameliorate brain inflammation and in the best case, halt disease progression."
"The caveat for this approach is to find the optimal time point to start the treatment," he said. "Since the treatment aims to prevent progression rather than reverse cognitive decline, patients should be treated when first symptoms of mild cognitive impairment occur. To identify these first signs could be challenging. Close interaction with patients' families will be helpful to determine early signs of cognitive changes."
Further, he added, "Even though the drugs that will be used in the trial are FDA-approved, it is not known if they work in an Alzheimer's patient's brain as expected."
SOURCE: https://go.nature.com/3qmWMJd Nature Aging, online December 10, 2021.
By Marilynn Larkin
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