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Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease

Jean C. Cruz Hernández, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer
doi: https://doi.org/10.1101/226886
Jean C. Cruz Hernández
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Oliver Bracko
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Calvin J. Kersbergen
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Victorine Muse
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Mohammad Haft-Javaherian
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Maxime Berg
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Laibaik Park
3Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Lindsay K. Vinarcsik
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Iryna Ivasyk
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Yiming Kang
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Marta Cortes-Canteli
4Patricia and John Rosenwald Laboratory for Neurobiology and Genetics, The Rockefeller University, New York, NY, USA
5Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
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Myriam Peyrounette
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Vincent Doyeux
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Amy Smith
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Joan Zhou
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Gabriel Otte
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Jeffrey D. Beverly
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Elizabeth Davenport
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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Yohan Davit
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Sidney Strickland
4Patricia and John Rosenwald Laboratory for Neurobiology and Genetics, The Rockefeller University, New York, NY, USA
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Costantino Iadecola
3Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
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Sylvie Lorthois
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
2Institut de Mécanique des Fluides de Toulouse (IMFT), Université de Toulouse, CNRS, INPT, UPS, Toulouse, France
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Nozomi Nishimura
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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  • For correspondence: nn62@cornell.edu cs385@cornell.edu
Chris B. Schaffer
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
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  • For correspondence: nn62@cornell.edu cs385@cornell.edu
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Abstract

The existence of cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models has been known for decades, but the underlying mechanisms and the resulting impacts on cognitive function and AD pathogenesis remain poorly understood. In the APP/PS1 mouse model of AD we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to leukocytes that adhered in capillary segments and blocked blood flow. These capillary stalls were an early feature of disease development, appearing before amyloid deposits. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. Our work has thus identified a cellular mechanism that explains the majority of the CBF reduction seen in a mouse model of AD and has also demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing the leukocyte adhesion that plugs capillaries may provide a novel strategy for improving cognition in AD patients.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted November 29, 2017.
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Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease
Jean C. Cruz Hernández, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer
bioRxiv 226886; doi: https://doi.org/10.1101/226886
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Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease
Jean C. Cruz Hernández, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer
bioRxiv 226886; doi: https://doi.org/10.1101/226886

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