Study preserves memory in mice, offering promising new basis for active immunization against Alzheimer's disease

Date:
May 3, 2022
Source:
University of Kansas
Summary:
During experiments in animal models, researchers have discovered
a possible new approach to immunization against Alzheimer's
disease. Their method uses a recombinant methionine (Met)-rich
protein derived from corn that was then oxidized in vitro to
produce the antigen: methionine sulfoxide (MetO)-rich protein.



FULL STORY ========================================================================== During experiments in animal models, researchers at the University of
Kansas have discovered a possible new approach to immunization against Alzheimer's disease (AD).


========================================================================== Their method uses a recombinant methionine (Met)-rich protein derived from
corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body,
goads the immune system into producing antibodies against the MetO
component of beta-amyloid, a protein that is toxic to brain cells and
seen as a hallmark of Alzheimer's disease. The findings have been just published in the peer-reviewed open-access journal Antioxidants.

"As we age, we have more oxidative stress, and then beta-amyloid and
other proteins accumulate and become oxidized and aggregated -- these
proteins are resistant to degradation or removal," said lead researcher
Jackob Moskovitz, associate professor of pharmacology & toxicology at
the KU School of Pharmacy.

"In a previous 2011 published study, I injected mouse models of
Alzheimer's disease with a similar methionine sulfoxide-rich protein and
showed about 30% reduction of amyloid plaque burden in the hippocampus,
the main region where damage from Alzheimer's disease occurs."
The MetO-rich protein used by Moskovitz for the vaccination of AD-model
mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn- based MetO-rich protein (antigen) fosters
the body's immune system to produce and deploy the antibodies against
MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.

In the new follow-up study, Moskovitz and his co-authors injected the
MetO-rich protein into 4-month-old AD-model mice that were genetically
modified to develop the familial form of Alzheimer's disease. Subsequent testing showed that this approach provoked the mice's immune systems into producing antibodies that could alleviate the presence of AD phenotypes
at an older age (10-month- old mice).

"This treatment induced the production of anti-MetO antibody in
blood-plasma that exhibits a significant titer up to at least 10 months
of age," according to the authors.



========================================================================== Moskovitz's KU co-authors on the Antioxidants study are Adam Smith,
assistant professor of pharmacology & toxicology; Kyle Gossman and
Benjamin Dykstra, graduate students in Smith's lab; and Philip Gao,
director of the Protein Production Group at the Del Shankel Structural
Biology Center.

In a series of tests, the KU researchers assessed the memory of injected
mice against similar mice that didn't receive the corn-based methionine sulfoxide.

"We measured short-term memory capability through a 'Y' maze, and
that's very important in Alzheimer's disease -- because when people
get Alzheimer's, their short-term memory is going away, while the old
memories are still there," Moskovitz said. "You put a mouse in a maze
shaped like a 'Y' so they can go either the left or right arm. But then
you introduce a third arm in the middle and if they recognize the third
arm as new, they'll spend more time exploring that new arm because they
have curiosity. If they don't even notice there's a third arm -- because
they forget it the minute after they saw it -- they will spend more
time in right or left." According to Moskovitz, there was a roughly 50% improvement in the memory of mice injected with the methionine sulfoxide (MetO)-rich protein versus the control.

In another experiment, mice were tasked with locating a platform in a
water maze.



==========================================================================
"We gave them six days to learn, and even the ones with Alzheimer's
eventually learn the location of the platform -- but we found after
the second day there was a big difference, the injected mice with
the antigen learn much faster than the nonimmunized mice," Moskovitz
said. "Then we remove the platform to see if they remember where the
platform was just by memory, not by looking. And again, we saw a big difference. The antigen-immunized mice remember and spend more time
in the vicinity of the platform they were trained on compared to the nonimmunized control mice." In addition to short-term memory improvement,
the study showed the antigen- injected mice exhibited better long memory capabilities, reduced beta-amyloid levels in both blood-plasma and the
brain, as well as "reduced beta-amyloid burden and MetO accumulations
in astrocytes in hippocampal and cortical regions; reduced levels of
activated microglia; and elevated antioxidant capabilities (through
enhanced nuclear localization of the transcription factor Nrf2) in the
same brain regions." The researchers found the data collected in the
study likely are translational, suggesting active immunization "could
give a possibility of delaying or preventing AD onset." Moskovitz said
such an immunization could be given to people as the risk of Alzheimer's disease increases later in life, "around the time people are told to go
get a colonoscopy for the first time in their 50s or 60s," he said.

"Further booster shots could maintain immunization, a process which people
are so familiar with from the COVID vaccines." An active immunization
would represent an improvement over current passive immunization regimes because the methionine sulfoxide antigen prods the immune system into
producing its own antibodies. In passive immunization, antibodies are
directly injected into the body but can have severe toxic side effects
(such as brain encephalitis) as well as being prone to rejection by the
immune system as non-self-antibodies over time.

Moskovitz said the next steps in this line of research would be to
conduct pre- clinical and clinical trials in humans in conjunction with
the sponsorship of interested pharmaceutical companies.


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


========================================================================== Journal Reference:
1. Adam S. Smith, Kyle R. Gossman, Benjamin Dykstra, Fei Philip Gao,
Jackob
Moskovitz. Protective Effects against the Development of Alzheimer's
Disease in an Animal Model through Active Immunization with
Methionine- Sulfoxide Rich Protein Antigen. Antioxidants, 2022;
11 (4): 775 DOI: 10.3390/antiox11040775 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220503141332.htm

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