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

Cruz Hernandez, J. C.; Bracko, O.; Kersbergen, C. J.; Muse, V.; Haft-Javaherian, M.; Berg, M.; Park, L.; Vinarcsik, L. K.; Ivasyk, I.; Kang, Y.; Cortes-Canteli, M.; Peyrounette, M.; Doyeux, V.; Smith, A.; Zhou, J.; Otte, G.; Beverly, J. D.; Davenport, E.; Davit, Y.; Strickland, S.; Iadecola, C.; Lorthois, S.; Nishimura, N.; Schaffer, C. B.

doi:10.1101/226886

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bioRxiv · 10.1101/226886

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

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Abstract

The existence of cerebral blood flow (CBF) reductions in Alzheimers 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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Cruz Hernandez, J. C., Bracko, O., Kersbergen, C. J., Muse, V., Haft-Javaherian, M., Berg, M., Park, L., Vinarcsik, L. K., Ivasyk, I., Kang, Y., Cortes-Canteli, M., Peyrounette, M., Doyeux, V., Smith, A., Zhou, J., Otte, G., Beverly, J. D., Davenport, E., Davit, Y., Strickland, S., Iadecola, C., Lorthois, S., Nishimura, N., Schaffer, C. B.. 2017-11-29. Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease. https://doi.org/10.1101/226886

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