Abstract As a neurodegenerative disease affecting a growing number of people in the U.S. and worldwide each year, Alzheimer's disease (AD) is marked by a series of pathophysiological features in the cortex and hippocampus, ultimately leading to cognitive dysfunction and dementia. Importantly, while the frequency of AD increases as the population ages, there is a lack of effective treatment options for mitigating the development or progression of this disease, which will lead to an enormous financial and healthcare burden on society in the coming decades as well as decreased quality of life for those patients and their primary caregivers. Understanding the contributing factors to the development of this disease is imperative to enable the development of an array of therapeutics to alleviate this growing crisis in the ageing population. Neuroinflammation is recognized to be associated with the development of AD and AD-related pathophysiology, and immune cells to play roles in this process. Peripheral leukocytes have been suggested to contribute to this neuroinflammatory response and impact the development of AD-related pathophysiology, although the extent to which they play a role in this process remains uncertain. Thus, we aim to characterize peripheral leukocyte accumulation in the cortical- hippocampal regions in a model of AD toward the development of novel therapeutics to modulate their responsiveness to AD-related pathophysiology. Our recent work has demonstrated that deletion of leukocyte- expressed β2AR leads to alterations in immune cell localization and responsiveness to injury. Notably, these effects were mediated via G protein-coupled receptor kinase (GRK)/β-arrestin (βarr)-dependent signaling, as expression of a GRK/βarr-coupled, but not a G protein-coupled, β2AR was capable of restoring normal leukocyte parameters. Translationally, we demonstrated that β-blockers with selectivity toward β2AR exert the same molecular effects on leukocytes and response to injury in mice and in human leukocytes and lymphoid tissues. In relation to these observations, studies have reported beneficial effects of β-blockers on AD-related neuropathology in humans and animal models of AD, however the specific impact of peripheral leukocyte- expressed β2AR on these effects is not known. Thus, we aim to determine whether leukocyte-expressed β2AR impacts the progression of AD-related pathophysiology via regulation of leukocyte accumulation in the cortical and hippocampal regions of the brain. Overall, we hypothesize that inflammatory peripheral leukocytes are differentially recruited into the cortex/hippocampus at different timepoints during disease progression and that leukocyte-specific deletion of β2AR will reduce the development and progression of AD-related neuropathology. Further, we hypothesize that GRK/βarr-biased β2AR signaling in particular will be responsible for these effects, representing a novel therapeutic direction in which to dampen the progress...