Author ORCID Identifier

https://orcid.org/0000-0003-2905-3512

Semester

Fall

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Randy Nelson

Committee Member

Aminata Coulibaly

Committee Member

James Simpkins

Committee Member

Kate Weil

Committee Member

Gordon Meares

Committee Member

Margaret Bennewitz

Abstract

Alzheimer’s disease (AD) is characterized not only by amyloid-β (Aβ) accumulation and cognitive decline, but also by complex neuroimmune dynamics. While most research has focused on glial cells, emerging evidence positions peripheral immune cells, particularly neutrophils, as influential modulators of disease progression. In both mouse models and human studies, neutrophils have been shown to actively participate in AD pathology through Aβ plaque interaction, neutrophil extracellular trap (NET) formation, and the release of pro-inflammatory factors. In transgenic AD mice (5xFAD, 3xTg, and APP/PS1), neutrophils infiltrate the brain and can be found around Aβ plaques, where they release reactive oxygen species (ROS), myeloperoxidase (MPO), and NETs, all of which contribute to neuroinflammation and vascular dysfunction. Depleting neutrophils or blocking their recruitment to the brain in these AD models increases cortical blood flow, reduces plaque burden, and improves cognitive function. In human AD patients, elevated levels of neutrophil markers, including MPO and S100A8, are found in the brain, and peripheral neutrophil counts or activation signatures correlate with disease severity and cognitive decline. In this dissertation, we investigated how neutrophil JAK2/STAT3 signaling shapes their functional behavior and contributes to 3xTg-AD mouse model pathology and health outcomes. First, in vitro experiments revealed that JAK2 in neutrophils regulate cytoskeletal rearrangement and ROS release in young, but not aged, mice. However, JAK2 was shown to regulate glycolytic metabolism in both young and aged neutrophils, through distinct mechanisms. These age-dependent differences in functional output points to a loss/dampening of JAK-regulation of neutrophil function with aging. Building on these mechanistic insights, a longitudinal in vivo study was conducted using bone marrow chimeras to selectively manipulate JAK2 (gain-of-function) and STAT3 (loss-of-function) signaling in neutrophils of 3xTg-AD mice. Neutrophils isolated from 3xTg mice have shown to exhibit age-related dysfunction, including reduced Aβ phagocytosis and diminished inflammatory responsiveness. Therefore, modulating their signaling pathways may help restore these essential functions, potentially leading to improved disease outcomes. Both interventions stabilized spatial working memory, improved survival and white matter integrity, but via divergent mechanisms. STAT3-deficient neutrophils decreased Aβ burden, improved whole brain volume, and enhanced oligodendrocyte and axon density, likely by suppressing neurotoxic inflammatory functions and promoting non-canonical STAT3-mediated signaling in early stages of disease. In contrast, JAK2-activated neutrophils increased Aβ association and increased the likelihood of astrocyte-mediated clearance, leading to late-stage improvements in survival, spatial working memory, and white matter health. These findings demonstrate that targeted modulation of neutrophil activity, either by amplifying or suppressing their inflammatory responses, can positively impact AD progression, with therapeutic effects varying based on the sex and stage of disease (early vs. late). Together, these findings challenge the long-standing notion that inflammation is uniformly detrimental in AD. Instead, they underscore the therapeutic potential of fine-tuning peripheral immune signaling, particularly JAK2/STAT3 pathway, to restore homeostatic functions in neutrophils and mitigate neurodegenerative pathology.

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