Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting approximately seven million Americans. It is marked by hyperphosphorylated-Tau, amyloid-beta aggregation, and cognitive decline. As the disease progresses, changes are observed in the brain, including brain volume, cortical thickness reduction, and ventricular enlargement. 

Recent evidence has implicated the role of the peripheral immune system in AD pathology. Neutrophils are the most abundant peripheral immune cell. In this project, various studies show that neutrophils infiltration in AD leads to poor cognitive performance. In our lab, we are interested in understanding how neutrophil activity and recruitment, through JAK/STAT activation, contribute to this pathology. 

Our preliminary data show that JAK2 activation plays a role in neutrophil migration. Therefore, we hypothesize that changing JAK2 activity, upregulation and downregulation, in neutrophils will change (increase and decrease, respectively) brain morphological changes associated with AD pathology. To test this hypothesis, we generated AD mice with overactive JAK2 or non-functional STAT3 (intracellular effector of JAK2) in neutrophils. Monthly whole brain, cortex, and ventricle volume were assessed using a small animal MRI. 

Preliminary findings show that JAK2 overactivation in neutrophils alters brain anatomy in a sex-specific manner. AD female mice with either overactive JAK2 or deficient STAT3 neutrophils maintain their whole brain volumes through disease progression. Specifically, volumes stay similar to wildtype controls and never decrease as observed in AD controls. These results suggest neutrophil activation, through JAK2 signaling, influences AD pathology in a sex-dependent manner.