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

Cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences on AD 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 wildtype animals, largely due to neutrophils that adhered in capillary segments and blocked blood flow. 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. This study identified a novel cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of AD and demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a novel strategy for improving cognition in AD patients.