Scientists identify malfunctioning brain cells as potential target for Alzheimer's treatment

Date:
December 10, 2021
Source:
Wake Forest Baptist Medical Center
Summary:
Scientists have identified a rare population of potentially toxic
senescent cells in human brains that can serve as a target for a
new Alzheimer's disease treatment.



FULL STORY ==========================================================================
For the first time, scientists have identified a rare population of
potentially toxic senescent cells in human brains that can serve as a
target for a new Alzheimer's disease treatment.


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The study, published in the Dec.10 edition of the journal Nature Aging,
was led by 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, and Habil Zare,
Ph.D., assistant professor of cell systems and anatomy, at University
of Texas Health San Antonio. The study was funded by the U.S. Department
of Veterans Affairs and National Institute on Aging.

Senescent cells are old, sick cells that cannot properly repair
themselves and don't die off when they should. Instead they 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, neurocognitive
decline and cancer.

Research conducted by Orr in 2018 found that senescent cells accumulated
in mouse models of Alzheimer's disease where they 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.

"However, until now, we didn't know to what extent senescent cells
accumulated in the human brain, and what they actually looked like,"
Orr said. "It was somewhat like looking for the proverbial needle
in a haystack except we weren't sure what the needle looked like."
Using sophisticated 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' plan was to first determine
if senescent cells were there, then how many there were and what types
of cells they were. They succeeded.



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The team found that approximately 2% of the brain cells were senescent
and also identified the type of cell and the characteristic features.

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

Next, Orr's team sought to determine if the senescent neurons had tangles
- - abnormal accumulations of a protein called tau that can collect
inside neurons in Alzheimer's disease. These tangles closely correlate
with disease severity, meaning that the more tangles individuals have
in their brains, the worse their memory, Orr said.

The researchers found that the senescent neurons not only had tangles
but that they overlapped to the point that it was hard to distinguish
between them.

Lastly, the team validated the findings by examining a different cohort
of postmortem brain tissue samples from people with Alzheimer's.



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"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," Orr said.

Orr is in the process of 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 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, University of Texas
Health in San Antonio and the Mayo Clinic. The three sites will again collaborate on the ADDF-funded clinical trial, Orr said.

"Dr. Orr's innovative 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, M.D., founding executive director and
chief science officer of the Alzheimer's Drug Discovery Foundation.

"Dr. Orr and her team are paving the way in senolytics research
for Alzheimer's disease, opening up a new target for potential
treatments. 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 buildup of toxic senescent cells -that contribute to Alzheimer's disease." 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.

========================================================================== Story Source: Materials provided by
Wake_Forest_Baptist_Medical_Center. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. 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, Miranda
E. Orr. Profiling senescent cells in human brains reveals neurons
with CDKN2D/p19 and tau neuropathology. Nature Aging, 2021; DOI:
10.1038/s43587-021-00142-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211210113016.htm

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