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

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.

SUBMITTER: Cruz Hernandez JC

PROVIDER: S-EPMC6508667 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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 JC Bracko Oliver O Kersbergen Calvin J CJ Muse Victorine V Haft-Javaherian Mohammad M Berg Maxime M Park Laibaik L Vinarcsik Lindsay K LK Ivasyk Iryna I Rivera Daniel A DA Kang Yiming Y Cortes-Canteli Marta M Peyrounette Myriam M Doyeux Vincent V Smith Amy A Zhou Joan J Otte Gabriel G Beverly Jeffrey D JD Davenport Elizabeth E Davit Yohan Y Lin Charles P CP Strickland Sidney S Iadecola Costantino C Lorthois Sylvie S Nishimura Nozomi N Schaffer Chris B CB

Nature neuroscience 20190211 3

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 ...[more]

PMID: 30742116

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Dataset Information

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

Publications

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

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