Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models.

Journal: Cell reports
PMID: 39427315

Abstract

Computer-vision and machine-learning (ML) approaches are being developed to provide scalable, unbiased, and sensitive methods to assess mouse behavior. Here, we used the ML-based variational animal motion embedding (VAME) segmentation platform to assess spontaneous behavior in humanized App knockin and transgenic APP models of Alzheimer's disease (AD) and to test the role of AD-related neuroinflammation in these behavioral manifestations. We found marked alterations in spontaneous behavior in App and 5xFAD mice, including age-dependent changes in motif utilization, disorganized behavioral sequences, increased transitions, and randomness. Notably, blocking fibrinogen-microglia interactions in 5xFAD-Fgg mice largely prevented spontaneous behavioral alterations, indicating a key role for neuroinflammation. Thus, AD-related spontaneous behavioral alterations are prominent in knockin and transgenic models and sensitive to therapeutic interventions. VAME outcomes had higher specificity and sensitivity than conventional behavioral outcomes. We conclude that spontaneous behavior effectively captures age- and sex-dependent disease manifestations and treatment efficacy in AD models.

Authors

  • Stephanie R Miller
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: stephanie.miller@gladstone.ucsf.edu.
  • Kevin Luxem
    German Center for Neurodegenerative Diseases (DZNE), 39118 Bonn and Magdeburg, Germany; Department of Cellular Neuroscience, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), 39106 Magdeburg, Germany.
  • Kelli Lauderdale
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Pranav Nambiar
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Patrick S Honma
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Katie K Ly
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Shreya Bangera
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Mary Bullock
    Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • Jia Shin
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Nick Kaliss
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Yuechen Qiu
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Catherine Cai
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Kevin Shen
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • K Dakota Mallen
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Zhaoqi Yan
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA 94158, USA.
  • Andrew S Mendiola
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA 94158, USA.
  • Takashi Saito
    Hama Agricultural Regeneration Research Centre, Fukushima Agricultural Technology Center, Minamisoma, Fukushima, 975-0036, Japan.
  • Takaomi C Saido
    Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako-shi 351-0198, Japan.
  • Alexander R Pico
    Gladstone Institutes, San Francisco, California, United States of America.
  • Reuben Thomas
    Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
  • Erik D Roberson
    Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • Katerina Akassoglou
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA 94158, USA.
  • Pavol Bauer
    German Center for Neurodegenerative Diseases (DZNE), 39118 Bonn and Magdeburg, Germany; Department of Cellular Neuroscience, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), 39106 Magdeburg, Germany.
  • Stefan Remy
    German Center for Neurodegenerative Diseases (DZNE), 39118 Bonn and Magdeburg, Germany; Department of Cellular Neuroscience, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), 39106 Magdeburg, Germany; German Center for Mental Health (DZPG), 39118 Magdeburg, Germany.
  • Jorge J Palop
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jorge.palop@gladstone.ucsf.edu.

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