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Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models

Cruz Hernández, Jean C. and Bracko, Oliver and Kersbergen, Calvin J. and Muse, Victorine and Haft-Javaherian, Mohammad and Berg, Maxime and Park, Laibaik and Vinarcsik, Lindsay K. and Ivasyk, Iryna and Rivera, Daniel A. and Kang, Yiming and Cortes-Canteli, Marta and Peyrounette, Myriam and Doyeux, Vincent and Smith, Amy F. and Zhou, Joan and Otte, Gabriel and Beverly, Jeffrey D. and Davenport, Elizabeth and Davit, Yohan and Lin, Charles P. and Strickland, Sidney and Iadecola, Costantino and Lorthois, Sylvie and Nishimura, Nozomi and Schaffer, Chris B. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. (2019) Nature Neuroscience, 22. 413-420. ISSN 1097-6256

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Official URL: https://doi.org/10.1038/s41593-018-0329-4

Abstract

Cerebral blood flow (CBF) reductions in Alzheimer’s disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer’s disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer’s disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer’s disease patients.

Item Type:Article
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Other partners > Cornell University (USA)
Université de Toulouse > Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Laboratory name:
Funders:
European Commission - National Institutes of Health (USA) - Alzheimer’s Drug Discovery Foundation (USA) - BrightFocus Foundation (USA) - CALMIP - CALcul en MIdi-Pyrénées (FRANCE) - DFG German Research Foundation (GERMANY)
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Deposited On:22 Feb 2019 11:39

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