Study finds how our brains turn into smarter disease fighters
Immune cell discovery a new attack on Alzheimer's, neurological disorders


Date:
January 31, 2023
Source:
University of California - Irvine
Summary:
Combating Alzheimer's and other neurodegenerative diseases by
inserting healthy new immune cells into the brain has taken a leap
toward reality.

Neuroscientists have found a way to safely thwart the brain's
resistance to them, vaulting a key hurdle in the quest.


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FULL STORY ========================================================================== Combating Alzheimer's and other neurodegenerative diseases by inserting
healthy new immune cells into the brain has taken a leap toward reality.

Neuroscientists at the University of California, Irvine and the University
of Pennsylvania have found a way to safely thwart the brain's resistance
to them, vaulting a key hurdle in the quest.


========================================================================== Their discovery about brain cells called microglia heralds myriad
possibilities for treating and even preventing neurodegenerative
disorders. The team's paper appears in the Journal of Experimental
Medicine.

When microglia are healthy, they serve as the central nervous system's
resident front-line disease warriors. "However, there is overwhelming
evidence that they can become dysfunctional in many neurological
conditions," said Mathew Blurton- Jones, UCI professor of neurobiology & behavior and study co-lead author.

"Until recently, scientists have mainly been looking at the mechanisms
that drive microglial dysfunction and trying to find drugs to change
their activity.

But with this study, we've found a way to potentially harness microglia themselves to treat those diseases." Frederick "Chris" Bennett,
assistant professor of psychiatry at Penn and co- lead author, added:
"There is an obstacle because once our own microglia develop in the
location where they are supposed to be in our brains, they don't give
up that space. They block the ability to deliver new cells that would
take their place. If you want to insert donor microglia, you have to
deplete the host microglia to open up room." Bennett and his laboratory partnered with Blurton-Jones and his lab on the project.

Microglia depend on signaling by a protein on their surface called CSF1R
for their survival. The FDA-approved cancer drug pexidartinib has been
found to block that signaling, killing them. This process would seem
to offer a way to clear space in the brain to insert healthy donor
microglia. However, there is a dilemma -- unless the pexidartinib is
stopped before the donor microglia are added, it will eliminate them,
too. But once the drug is terminated, the host microglia regenerate too
fast to effectively put in the donor cells.

This quandary has challenged efforts to treat people with certain rare
and severe neurologic conditions. One is Krabbe disease, in which the
body's cells can't digest certain fats that are highly abundant in
the brain. Currently, clinicians use bone marrow transplantation and chemotherapy to try to introduce new immune cells similar to microglia
into the brain. But this approach can be toxic and must be carried out
before Krabbe symptoms manifest.

"Our team believed that if we could overcome the brain's resistance to accepting new microglia, we could successfully transplant them into
patients using a safer, more effective process in order to target a
great number of diseases," said co-first author Sonia Lombroso, a Penn
Ph.D. student and member of the Bennett Lab. "We decided to investigate
whether we could make the donor microglia resistant to the drug that
eliminates their host counterparts." The researchers used CRISPR
gene-editing technology to create one amino acid mutation, known as
G795A, which they introduced into donor microglia produced from human
stem cells or a mouse microglial cell line. Then they injected the donor microglia into humanized rodent models while administering pexidartinib,
with exciting results.

"We discovered that this one small mutation caused the donor microglia
to resist the drug and thrive, while the host microglia continued to die
off," said co-first author Jean Paul Chadarevian, a UCI Ph.D. student who
is a member of the Blurton-Jones Lab. "This finding could lead to many
options for developing new microglial-based treatments. Pexidartinib
is already approved for clinical use and appears to be relatively well tolerated by patients." Approaches could range from fighting disease
by replacing dysfunctional microglia with healthy ones to designing
microglia that can recognize imminent threats and strike against them
with therapeutic proteins before they cause harm.

The UCI-Penn team believes treatments based on this kind of microglial
method could be developed within a decade. Their next investigations
include studying in rodent models how to use the approach to attack
the brain plaques associated with Alzheimer's and to counter Krabbe and
other similar diseases.

Support for the project was provided by the National Institutes of Health, National Science Foundation, The Paul Allen Frontiers Group, Klingenstein- Simons Fellowship Award in Neuroscience and the Susan Scott Foundation.

* RELATED_TOPICS
o Health_&_Medicine
# Brain_Tumor # Immune_System # Diseases_and_Conditions
# Stem_Cells
o Mind_&_Brain
# Disorders_and_Syndromes # Alzheimer's #
Brain-Computer_Interfaces # Dementia
* RELATED_TERMS
o Polyphenol_antioxidant o Brain_tumor o Alzheimer's_disease o
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========================================================================== Story Source: Materials provided by
University_of_California_-_Irvine. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Jean Paul Chadarevian, Sonia I. Lombroso, Graham C. Peet, Jonathan
Hasselmann, Christina Tu, Dave E. Marzan, Joia Capocchi, Freddy S.

Purnell, Kelsey M. Nemec, Alina Lahian, Adrian Escobar, Whitney
England, Sai Chaluvadi, Carleigh A. O'Brien, Fazeela Yaqoob,
William H. Aisenberg, Matias Porras-Paniagua, Mariko L. Bennett,
Hayk Davtyan, Robert C.

Spitale, Mathew Blurton-Jones, F. Chris Bennett. Engineering an
inhibitor-resistant human CSF1R variant for microglia replacement.

Journal of Experimental Medicine, 2023; 220 (3) DOI:
10.1084/jem.20220857 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/01/230131183128.htm

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