New strategy reduces brain damage in Alzheimer's and related disorders,
in mice
Targeting inflammatory brain cell may be effective for brain diseases
linked to tau protein

Date:
March 18, 2022
Source:
Washington University School of Medicine
Summary:
Alzheimer's disease is the most common and best known of the
tauopathies, a set of neurodegenerative brain diseases caused
by toxic tangles of the protein tau. A study has now shown that
targeting astrocytes -- an inflammatory cell in the brain --
reduces tau-related brain damage and inflammation in mice.



FULL STORY ========================================================================== Alzheimer's disease is the most common and best known of the tauopathies,
a set of neurodegenerative brain diseases caused by toxic tangles of
the protein tau.

A study by researchers at Washington University School of Medicine in
St. Louis has shown that targeting astrocytes -- an inflammatory cell in
the brain - - reduces tau-related brain damage and inflammation in mice.


==========================================================================
The findings, available online in Science Translational Medicine,highlight
the pivotal role of astrocytes in driving brain damage in tauopathies, and
open up new avenues toward better therapies for the group of devastating
and difficult to treat conditions.

"Brain inflammation is emerging as a contributor to the development of Alzheimer's disease, and that inflammation is driven by non-neuronal
cells in the brain, including astrocytes," said senior author Gilbert
Gallardo, PhD, an assistant professor of neurology. "Our study highlights
that inflamed astrocytes are contributing to tau-associated pathologies
and suggests that suppressing their reactivity may be beneficial in
reducing brain inflammation and delaying Alzheimer's progression."
Tau, normally found inside neurons in the brain, helps form internal scaffolding that gives neurons their shape. When tau gets tangled,
though, it leads to brain inflammation, tissue damage and cognitive
decline. Tau forms tangles in people who carry mutations in the tau
gene or who have experienced assaults on the brain such as repeated
concussions or exposure to neurotoxic chemicals. In Alzheimer's, tau
tangles take shape relatively late in the disease process, apparently
triggered by earlier disease-related brain changes such as the buildup
of plaques of the protein amyloid beta.

In many neurodegenerative conditions, so-called reactive astrocytes -
- astrocytes activated in such a way that they cause harm to, rather
than protect, brain tissue -- are plentiful at sites of neuronal
damage. In previous work on amyotrophic lateral sclerosis (ALS), a neurodegenerative disease but not a tauopathy, Gallardo and colleagues identified an astrocyte protein that encouraged the cells to take on toxic characteristics and exacerbate brain inflammation. Gallardo suspected that
the protein, named alpha2-Na+/K+ adenosine triphosphatase (alpha2-NKA),
also may drive the toxicity of astrocytes in Alzheimer's disease and
other tauopathies.

Gallardo, first author Carolyn Mann, then a technician in Gallardo's lab,
and co-author Celeste Karch, PhD, an associate professor of psychiatry, obtained data on the expression level of the gene that codes for
alpha2-NKA. They studied brain samples from 80 people who had died
of Alzheimer's; 82 who had of died of a tauopathy called progressive supranuclear palsy (PSP); and 76 who had died of causes unrelated to neurodegeneration. The researchers found that alpha2-NKA was highly
expressed in people who had died of Alzheimer's or PSP compared with
those who had died of other causes, suggesting that the protein could
be a contributor to brain damage in both conditions.

To further investigate the role of alpha2-NKA, the researchers turned to
mice genetically engineered to start developing tau tangles by about 6
months of age. By 9 1/2 months of age, such animals' brains are damaged, atrophied and inflamed, and they have lost the ability to properly perform everyday tasks of rodent life such as building a nest. The researchers
found that, like people with tauopathies, the genetically modified mice
also had elevated levels of alpha2-NKA in their brains. The levels rose
as the mice got older and the inflammation and brain damage worsened.

Digoxin, a drug used to treat heart conditions, interferes with the
activity of alpha2-NKA. The researchers tested whether treating mice
with digoxin could reduce tau tangles, brain shrinkage and inflammation,
and behavioral changes.

The drug worked, and moreover, it worked whether they gave the compound
to mice under 6 months old, when the animals were just beginning to
develop tau tangles, or at 8 months, when the tangles and damage already
were established.

"The take-home message here is that suppressing the inflamed astrocytic
state halts disease progression," Mann said. "This is important because experimental therapeutics for Alzheimer's and related tauopathies
have focused largely on clearing pathological proteins that have been implicated in neuronal dysfunction and death. But our study gives evidence
that targeting inflamed astrocytes and brain inflammation may be the
key to successfully treating such conditions." While digoxin has been
approved by the Food and Drug Administration for certain heart conditions,
its effects on the brain must be studied more thoroughly before it can be evaluated as a potential therapy for Alzheimer's and related tauopathies, Gallardo said.


========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Carolyn N. Mann, Shamulailatpam Shreedarshanee Devi, Corey
T. Kersting,
Amber V. Bleem, Celeste M. Karch, David M. Holtzman, Gilbert
Gallardo.

Astrocytic a2-Na /K ATPase inhibition suppresses astrocyte
reactivity and reduces neurodegeneration in a tauopathy mouse
model. Science Translational Medicine, 2022; 14 (632) DOI:
10.1126/scitranslmed.abm4107 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220318131646.htm

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