MSGID: 1:317/3 62720172   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
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   During experiments in animal models, researchers at the University of   
   Kansas have discovered a possible new approach to immunization against   
   Alzheimer's disease (AD).   
      
      
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   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.   
      
      
      
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   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.   
      
      
      
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   "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.   
      
      
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   Story Source: Materials provided by University_of_Kansas. Note: Content   
   may be edited for style and length.   
      
      
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   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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