MSGID: 1:317/3 64927d01   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Restoring the blood-brain barrier?    
      
     Date:   
         June 20, 2023   
     Source:   
         Stanford Medicine   
     Summary:   
         Scientists discover a treatment in mice to repair the blood-brain   
         barrier, which is key to brain health.   
      
      
         Facebook Twitter Pinterest LinkedIN Email   
      
   ==========================================================================   
   FULL STORY   
   ==========================================================================   
   There's a bouncer in everyone: The blood-brain barrier, a layer of   
   cells between blood vessels and the rest of the brain, kicks out toxins,   
   pathogens and other undesirables that can sabotage the brain's precious   
   gray matter.   
      
   When the bouncer is off its guard and a rowdy element gains entry,   
   a variety of conditions can crop up. Barrier-invading cancer cells can   
   develop into tumors, and multiple sclerosis can occur when too many white   
   blood cells slip pass the barrier, leading to an autoimmune attack on   
   the protective layer of brain nerves, hindering their communication with   
   the rest of the body.   
      
   "A leaky blood-brain barrier is a common pathway for a lot of brain   
   diseases, so to be able to seal off the barrier has been a long   
   sought-after goal in medicine," said Calvin Kuo, MD, PhD, the Maureen   
   Lyles D'Ambrogio Professor and a professor of hematology.   
      
   Methods of repairing the blood-brain barrier remain understudied,   
   according to Kuo. But a recent paper he and colleagues led describes a   
   treatment that could be instrumental in restoring the barrier's normal   
   function. Kuo is the senior author of the paper, published in Nature   
   Communications on June 2.   
      
   "We have evaluated a new therapeutic class of molecules that can be   
   used to treat a leaky blood-brain barrier; previously, there were no   
   treatments directed at the blood-brain barrier specifically," Kuo said.   
      
   The researchers started their quest by looking at WNT signaling, a   
   communication pathway used by cells to promote tissue regeneration and   
   wound healing. WNT signaling helps maintain the blood-brain barrier by   
   promoting cell-to-cell communication that lines brain blood vessels.   
      
   "There's a lot of historical data that indicated that the WNT signaling   
   pathway would be important for maintaining the blood-brain barrier,"   
   Kuo said. "The opportunity arose to test a novel WNT signaling pathway   
   that would turn on signaling in the blood-brain barrier by binding   
   very selectively to a receptor called frizzled."  Scientists have been   
   focusing on frizzled, a protein receptor that initiates the WNT pathway,   
   for blood-brain barrier therapies since mouse mutations in the frizzled   
   gene cause blood-brain barrier abnormalities.   
      
   How it's made Many different molecules bind to frizzled protein receptors,   
   so to narrow their search for a potential therapeutic molecule, the   
   researchers selected only those that specifically target cells that line   
   the brain's blood vessels.   
      
   Chris Garcia, PhD, a professor of molecular and cellular physiology as   
   well as the Younger Family Professor, developed prototype therapeutic   
   WNT pathway molecules in the lab, including a molecule that activates   
   the frizzled receptor FZD4. Building off of the work of Garcia and Kuo,   
   collaborators at a research company created L6-F4-2, a FZD4 binding   
   molecule that activates WNT signaling 100 times more efficiently than   
   other FZD4 binders.   
      
   When the team, including Jie Ding, a research scientist and the lead   
   author of the paper, activated WNT signaling at a higher rate, they saw   
   an increase in blood-brain barrier strength.   
      
   Keeping the bouncer on duty The researchers wanted to study what happens   
   when the natural molecular key for frizzled is missing, and whether it   
   can be replaced successfully with L6-F4-2.   
      
   So they turned to Norrie disease, a genetic abnormality that results in   
   a leaky blood-retinal barrier.   
      
   The blood-retinal barrier performs the same function for the eye as   
   the blood- brain barrier does for the brain. In Norrie disease, the   
   development of blood vessels of the retina -- the layer of light-sensitive   
   cells in the back of the eye -- is hindered, resulting in leaky blood   
   vessel connections, improper development and blindness.   
      
   Norrie disease results from mutations in the NDP gene, which provides   
   instructions for making a protein called Norrin, which is the key that   
   fits the lock of the FZD4receptor and turns it on. In the study's mice,   
   the gene is inactivated, and the key is missing causing a leaky barrier   
   and blindness. The scientists replaced the missing Norrin protein with   
   L6-F4-2, which they call a surrogate.   
      
   When L6-F4-2 replaced the missing Norrin protein, the blood-retinal   
   layer was restored in the mice. Researchers knew this because they   
   imaged the blood vessels and found them to be denser, and less leaky,   
   than before treatment.   
      
   Scientists also showed that, for the blood-brain barrier surrounding   
   the mice cerebellum -- a region responsible for muscle coordination --   
   L6-F4-2 replaced Norrin and activated WNT signaling.   
      
   Next, the researchers wanted to study a more common human condition --   
   ischemic stroke (in which blood vessels and the blood-brain barrier are   
   damaged, and fluid, blood and inflammatory proteins involved in cellular   
   communication can leak into the brain. They found that L6-F4-2 reduced   
   the severity of stroke and improved survival of mice compared with mice   
   that had untreated strokes.   
      
   Importantly, L6-F4-2 reversed the leakiness of brain blood vessels   
   after stroke. Mice treated with L6-F4-2 had increased stroke survival,   
   compared to those that were not treated.   
      
   The finding shows that, in mice, the blood-brain barrier could be restored   
   by drugs that activate FZD receptors and the WNT signaling pathway.   
      
   Because a variety of disorders have their origin in blood-brain barrier   
   dysfunction, Kuo is excited about the treatment potential for a variety   
   of other neurological diseases, such as Alzheimer's, multiple sclerosis   
   and brain tumors.   
      
   "We hope this will be a first step toward developing a new generation   
   of drugs that can repair the blood-brain barrier, using a very different   
   strategy and molecular target than current medications," Kuo said.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Brain_Tumor # Hypertension # Blood_Clots # Anemia   
             o Mind_&_Brain   
                   # Brain_Injury # Brain-Computer_Interfaces #   
                   Disorders_and_Syndromes # Neuroscience   
       * RELATED_TERMS   
             o Stroke o Peripheral_nervous_system o Cerebral_contusion   
             o Brain_damage o West_Nile_virus o Brain_tumor o   
             Deep_brain_stimulation o Amygdala   
      
   ==========================================================================   
   Story Source: Materials provided by Stanford_Medicine. Original written   
   by Emily Moskal.   
      
   Note: Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Jie Ding, Sung-Jin Lee, Lukas Vlahos, Kanako Yuki, Cara C. Rada,   
      Vincent   
         van Unen, Meghah Vuppalapaty, Hui Chen, Asmiti Sura, Aaron   
         K. McCormick, Madeline Tomaske, Samira Alwahabi, Huy Nguyen, William   
         Nowatzke, Lily Kim, Lisa Kelly, Douglas Vollrath, Andrea Califano,   
         Wen-Chen Yeh, Yang Li, Calvin J. Kuo. Therapeutic blood-brain   
         barrier modulation and stroke treatment by a bioengineered   
         FZD4-selective WNT surrogate in mice. Nature Communications, 2023;   
         14 (1) DOI: 10.1038/s41467-023-37689-1   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/06/230620113821.htm   
      
   --- up 1 year, 16 weeks, 1 day, 10 hours, 50 minutes   
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)   
   SEEN-BY: 15/0 106/201 114/705 123/120 153/7715 218/700 226/30 227/114   
   SEEN-BY: 229/110 112 113 307 317 400 426 428 470 664 700 291/111 292/854   
   SEEN-BY: 298/25 305/3 317/3 320/219 396/45 5075/35   
   PATH: 317/3 229/426