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Nat Neurosci. 2019 Mar;22(3):413-420. doi: 10.1038/s41593-018-0329-4. Epub 2019 Feb 11.

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

Author information

1
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
2
Institut de Mécanique des Fluides de Toulouse, Université de Toulouse, CNRS, INPT, UPS, Toulouse, France.
3
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
4
Patricia and John Rosenwald Laboratory for Neurobiology and Genetics, The Rockefeller University, New York, NY, USA.
5
Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
6
Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
7
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA. nn62@cornell.edu.
8
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA. cs385@cornell.edu.

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.

PMID:
30742116
DOI:
10.1038/s41593-018-0329-4

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