Project I: Summary Chronic systemic inflammation and immune activation are associated with Alzheimer’s disease (AD) pathogenesis, and neuroinflammation mediated by astrocytes and microglia is observed in the brain prior to the onset of cognitive decline. However, there is a need to delineate contributions of other inflammatory cells to AD, particularly those that can be targeted in the periphery. The overall goals for this study are to 1) determine if altered neutrophil lifespan exacerbates neuroinflammation and cognitive decline in AD mouse models, and 2) investigate neutrophil cell death as a potential therapeutic target in AD. There is strong published evidence that neutrophils are dysregulated in AD and exacerbate disease pathogenesis. In humans and AD mouse models, neutrophils infiltrate the brain vasculature and parenchyma and neutrophil activation in the periphery corresponds with disease progression. In addition, several studies have demonstrated that depleting neutrophils results in cognitive improvement in a familial AD mouse model. While aberrant neutrophil responses damage tissue and contribute to neurodegeneration, appropriate responses could be helpful in containing inflammatory stimuli (e.g., infection, amyloid beta, myelin debris) and participate in tissue repair. This balance between damage and beneficial physiological function is maintained by tightly regulated neutrophil lifespan. Under homeostatic conditions, neutrophils are short-lived, spending only a few hours in circulation on average. Our hypothesis is that delayed neutrophil apoptosis in AD contributes to increased neutrophils, neutrophil-mediated inflammation, and AD pathogenesis. This hypothesis is based on compelling evidence from published work and our preliminary data. The pathways that regulate neutrophil apoptosis are dysregulated in Alzheimer’s disease (MAPK and NFkb/TNFa signaling). In addition, delayed neutrophil apoptosis has been shown to result in increased neutrophil extracellular trap (NET) release, and NET release is a component of AD pathogenesis. Finally, our preliminary data demonstrate that neutrophil apoptosis is altered in AD mouse models and this associates with markers of NET release. We will address our hypothesis and achieve our study goals by pursuing the following two aims: 1) Investigate the hypothesis that altered neutrophil apoptosis is a therapeutic target in AD using mouse models; and 2) Determine if neutrophil apoptosis and NETosis are altered in persons with AD. This project is significant and transitionally innovative because neutrophil apoptosis represents a promising therapeutic target based on the following: 1) apoptosis and clearance of neutrophils are fundamental to the resolution of inflammation, a known factor in AD pathogenesis; 2) promoting neutrophil apoptosis can dampen inflammation without severely compromising host defense; and 3) neutrophils can be targeted in the periphery. The data from these aims will provide the found...