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

Jean Cruz Hernández (1) , Oliver Bracko (1) , Calvin Kersbergen (1) , Victorine Muse (1) , Mohammad Haft-Javaherian (1) , Maxime Berg (2) , Laibaik Park (3) , Lindsay Vinarcsik (1) , Iryna Ivasyk (1) , Daniel Rivera (1) , Yiming Kang (1) , Marta Cortes-Canteli (4) , Myriam Peyrounette (2) , Vincent Doyeux (2) , Amy Smith (2) , Joan Zhou (1) , Gabriel Otte (1) , Jeffrey Beverly (1) , Elizabeth Davenport (1) , Yohan Davit (2) , Charles Lin (5) , Sidney Strickland (6) , Costantino Iadecola (3) , Sylvie Lorthois (1, 2) , Nozomi Nishimura (1) , Chris Schaffer (1)

1 Cornell University [New York]
2 IMFT - Institut de mécanique des fluides de Toulouse
3 Weill Cornell Medicine [Cornell University]
4 CNIC - Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain]
5 Massachusetts General Hospital [Boston]
6 Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University

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.

Mots clés: Neutrophil; brain capillaries; Alzheimer’s disease; Brain Microcirculation; Cerebral Blood Flow; In vivo experiments; Animal models; TPSLM; Modeling and simulation; Network model; Capillary occlusions; Alzheimer's disease; Neutrophils

Domaines: Dynamique des Fluides [physics.flu-dyn]; Cardiologie et système cardiovasculaire; Mécanique des fluides [physics.class-ph]

Jean Cruz Hernández, Oliver Bracko, Calvin Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, et al.. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models.. Nature Neuroscience, 2019, 22 (3), pp.413-420. ⟨10.1038/s41593-018-0329-4⟩. ⟨hal-02391317⟩