Could aid efforts to find treatments for Alzheimer’s dementia and other diseases.
By WASHINGTON UNIVERSITY SCHOOL OF
MEDICINE
A
new druggable pathway that potentially could be used to help prevent Alzheimer’s dementia has been discovered by
researchers at Washington University School of Medicine in St. Louis.
Amyloid
beta accumulation in the brain is believed to be the first step in the
development of Alzheimer’s dementia. Researchers have poured countless hours
and millions of dollars into finding ways to clear amyloid away before
cognitive symptoms arise. Unfortunately, the results have been largely
disappointing.
In this study, scientists found a way to increase the clearance of waste products from the brains of mice by ramping up a genetic quirk known as readthrough. According to the researchers, this same strategy also may be effective for other neurodegenerative diseases characterized by the buildup of toxic proteins, such as Parkinson’s disease. The study was published on August 24, 2022, in the journal Brain.
Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. At first, Darshan Sapkota, PhD thought this tail represented nothing more than an occasional failure of quality control in the protein-manufacturing process. Sapkota led this study while a postdoctoral researcher at Washington University but is now an assistant professor of biological sciences at the University of Texas, Dallas.
“We were studying this very wonky basic science question — ‘How do proteins get made?’ — and we noticed this funny thing,” said senior author Joseph D. Dougherty, PhD, a Washington University professor of genetics and of psychiatry, and Sapkota’s former mentor.
“Sometimes the protein-synthesizing machinery blew right through the stop sign at the end and made this extra bit on the end of aquaporin 4. At first, we thought it couldn’t possibly be relevant. But then we looked at the gene sequence, and it was conserved across species. And it had this really striking pattern in the brain: It was only in structures that are important for waste clearance. So that’s when we got excited.”
Scientists
already knew that occasionally the cell’s protein-building machinery fails to
stop where it should. When the machinery doesn’t stop — a phenomenon called
readthrough — it creates extended forms of proteins that sometimes function
differently than the regular forms.
Sapkota
and Dougherty created special tools to see whether the long form of aquaporin 4
behaved differently in the brain than the regular form. They discovered the
long form — but not the short one — in the so-called endfeet of astrocytes.
Astrocytes are a kind of support cell that help maintain the barrier between
the brain and the rest of the body. Their endfeet wrap around tiny blood
vessels in the brain and help regulate blood flow. Inside astrocytic endfeet is
the perfect place to be if your job is to keep the brain free of unwanted
proteins by flushing waste out of the brain and into the bloodstream, where it
can be carried away and disposed of.
Sapkota
though that increasing the amount of long aquaporin 4 might increase waste
clearance. Therefore, he screened 2,560 compounds for the ability to increase
readthrough of the aquaporin 4 gene. He found two: apigenin, a dietary flavone
found in chamomile, parsley, onions, and other edible plants; and
sulphaquinoxaline, a veterinary antibiotic used in the meat and poultry
industries.
Sapkota
and Dougherty teamed up with Alzheimer’s researchers and co-authors John
Cirrito, PhD, an associate professor of neurology, and Carla Yuede, PhD, an
associate professor of psychiatry, of neurology, and of neuroscience, to figure
out the relationship between long aquaporin 4 and amyloid beta clearance.
The
scientists studied mice that were genetically engineered to have high levels of
amyloid in their brains. They treated the mice with apigenin;
sulphaquinoxaline; an inert liquid; or a placebo compound that has no effect on
readthrough. Mice treated with either apigenin or sulphaquinoxaline cleared
amyloid beta significantly faster than those treated with either of the two
inactive substances.
“There’s
a lot of data that says reducing amyloid levels by just 20% to 25% stops
amyloid buildup, at least in mice, and the effects we saw were in that
ballpark,” Cirrito said. “That tells me that this could be a novel approach to
treating Alzheimer’s and other neurodegenerative diseases that involve protein
aggregation in the brain. There’s nothing that says this process is specific
for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too,
which could benefit people with Parkinson’s disease.”
Sulphaquinoxaline
is not safe for use in people. Apigenin is available as a dietary supplement,
but it’s not known how much gets into the brain. Cirrito cautions against
consuming large amounts of apigenin in an attempt to stave off Alzheimer’s. The
scientists are working on finding better drugs that influence the production of
the long form of aquaporin 4, testing several derivatives of sulphaquinoxaline
and additional compounds.
“We’re
looking for something that could be quickly translated into the clinic,”
Sapkota said. “Just knowing that it’s targetable at all by a drug is a helpful
hint that there’s going to be something out there we can use.”
Reference:
“Aqp4 stop codon readthrough facilitates amyloid-β
clearance from the brain” by Darshan Sapkota, Colin Florian, Brookelyn M
Doherty, Kelli M White, Kate M Reardon, Xia Ge, Joel R Garbow, Carla M Yuede,
John R Cirrito and Joseph D Dougherty, 24 August 2022, Brain.
DOI:
10.1093/brain/awac199
This
work was supported by the National Institute of Neurological Disorders and
Stroke, grant number 1R01NS102272; the Mallinckrodt Institute of Radiology; the
Hope Center for Neurological Disorders; the National Institute on Aging, grant
numbers K99AG061231 and R01AG064902; Coins for Alzheimer’s Research Trust; and
the Rotary Club International.