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   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Astrocyte dysfunction causes cognitive decline    
      
     Date:   
         April 20, 2023   
     Source:   
         Weill Cornell Medicine   
     Summary:   
         People with dementia have protein build-up in astrocytes that may   
         trigger abnormal antiviral activity and memory loss, according to   
         a preclinical study.   
      
      
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   FULL STORY   
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   People with dementia have protein build-up in astrocytes that may trigger   
   abnormal antiviral activity and memory loss, according to a preclinical   
   study by a team of Weill Cornell Medicine investigators.   
      
      
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   Dysfunction in cells called neurons, which transmit messages throughout   
   the brain, has long been the prime suspect in dementia-related cognitive   
   deficits.   
      
   But a new study, published in Science Advances on April 19, suggests that   
   abnormal immune activity in non-neuronal brain cells called astrocytes is   
   sufficient to cause cognitive deficits in dementia. The discovery could   
   lead to new treatments that reduce excess immune activity in astrocytes   
   and their detrimental effects on other brain cells and cognition.   
      
   "Astrocyte dysfunction alone can drive memory loss, even when neurons   
   and other cells are otherwise healthy," said co-senior author Dr. Anna   
   Orr, the Nan and Stephen Swid Assistant Professor of Frontotemporal   
   Dementia Research in the Feil Family Brain and Mind Research Institute   
   and a member of the Helen and Robert Appel Alzheimer's Disease Research   
   Institute at Weill Cornell Medicine.   
      
   "We found, in mice, that astrocytes can cause cognitive decline through   
   their antiviral activities, which can make neurons hyperactive."  While   
   neurons have been intensively studied in dementia and other diseases,   
   much less research has focused on astrocytes, which many scientists   
   viewed as playing only supporting roles to neurons in brain health.   
      
   "We are very interested in the roles of astrocytes in cognitive   
   and behavioral disorders," she said. "These cells are prevalent in   
   the brain and perform various key functions, but their involvement   
   in neurocognitive disorders like dementia are poorly understood."   
   When the investigators, including first author Dr. Avital Licht-Murava,   
   a former postdoctoral associate in the Orr lab, examined tissue samples   
   from deceased individuals who were diagnosed with either Alzheimer's   
   disease or frontotemporal dementia, they found an accumulation of a   
   protein called TDP-43 in astrocytes within the hippocampus, a brain   
   region crucial for memory. To understand the effects of this protein   
   build-up, the team conducted a series of experiments in mouse models and   
   brain cells grown in the laboratory. Other senior investigators that   
   contributed to the study include Dr. Robert Schwartz at Weill Cornell   
   Medicine and Dr. Robert Froemke at New York University.   
      
   In mice, the build-up of TDP-43 in astrocytes was sufficient to cause   
   progressive memory loss but not other behavioral changes. "Astrocytes in   
   the hippocampus seem to be more vulnerable to this pathology." she said.   
      
   To understand the causes of memory loss at the molecular level, co-senior   
   author Dr. Adam Orr, an assistant professor of research in neuroscience   
   in the Feil Family Brain and Mind Research Institute and a member   
   of the Appel Alzheimer's Disease Research Institute at Weill Cornell   
   Medicine, analyzed gene expression and found high levels of antiviral   
   gene activities, even though no virus was present in the brain. Astrocytes   
   produced excessive amounts of immune messengers called chemokines, which   
   can activate CXCR3 chemokine receptors typically found on infiltrating   
   immune cells. To their surprise, the team discovered that CXCR3 receptor   
   levels were elevated in hippocampal neurons, and that excessive CXCR3   
   receptor activity made neurons "hyperactive," Dr. Anna Orr said.   
      
   "Blocking CXCR3 reduced neuronal firing in individual neurons and   
   eliminating CXCR3 in mice by genetic engineering alleviated cognitive   
   deficits caused by astrocytic TDP-43 build-up," Dr. Adam Orr said. These   
   experiments demonstrate that impaired astrocytes can have a detrimental   
   role in dementia, he said.   
      
   Both investigators were excited by the potential clinical implications   
   of their findings.   
      
   "For effective therapeutics, we need to consider astrocytes along with   
   neurons," Dr. Anna Orr said.   
      
   Drugs that target the identified immune pathways might help improve   
   cognitive function in people with dementia. She noted that scientists are   
   already testing CXCR3 blockers to treat arthritis and other inflammatory   
   conditions in clinical trials. These drugs could be tested and potentially   
   repurposed for dementia.   
      
   This study may also provide insights into how antiviral immune responses   
   can cause cognitive dysfunction. Previous research has linked viral   
   infections to Alzheimer's disease and to long-term neurocognitive   
   effects such as memory loss and brain fog. Abnormal immune activity   
   in astrocytes might contribute to these cognitive effects as well as   
   increase individuals' susceptibility to viral infections, which could   
   further worsen brain health and promote some cases of dementia.   
      
   The team is currently studying how TDP-43 alters antiviral activities   
   in astrocytes and whether these changes increase brain susceptibility   
   to viral pathogens.   
      
   "Astrocytes can promote resilience or vulnerability to brain disease,"   
   Dr. Anna Orr said. "Understanding how they enable cognitive function or   
   cause cognitive decline will be critical to understanding brain health   
   and developing effective therapies."   
       * RELATED_TOPICS   
             o Mind_&_Brain   
                   # Dementia # Intelligence # Disorders_and_Syndromes #   
                   Alzheimer's # Neuroscience # Brain_Injury # Psychology #   
                   Brain-Computer_Interfaces   
       * RELATED_TERMS   
             o Seizure o Multi-infarct_dementia o Dementia_with_Lewy_bodies   
             o Alzheimer's_disease o Bruxism o Dementia o Limbic_system   
             o Epilepsy   
      
   ==========================================================================   
   Story Source: Materials provided by Weill_Cornell_Medicine. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Avital Licht-Murava, Samantha M. Meadows, Fernando Palaguachi,   
      Soomin C.   
      
         Song, Stephanie Jackvony, Yaron Bram, Constance Zhou, Robert   
         E. Schwartz, Robert C. Froemke, Adam L. Orr, Anna G. Orr. Astrocytic   
         TDP-43 dysregulation impairs memory by modulating antiviral   
         pathways and interferon-inducible chemokines. Science Advances,   
         2023; 9 (16) DOI: 10.1126/sciadv.ade1282   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/04/230420135302.htm   
      
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