MSGID: 1:317/3 63d9eae6   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
             White_blood_cell o Excitotoxicity_and_cell_damage o Brain_damage   
             o Parkinson's_disease o Stroke   
      
   ==========================================================================   
   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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