Neutrophil-driven vascular inflammation in VCID and Mixed Alzheimer's Disease - Summary: Substantial reductions in brain blood flow are found in patients with and mouse models of neurodegenerative diseases, including Alzheimer’s Disease (AD). Vascular pathologies are prevalent in an aging population and patients with AD. Despite their importance, vascular contributions to cognitive impairment and dementia (VCID) and the interaction with AD are understudied. We have previously shown that neutrophils block blood vessels and contribute to blood flow reductions and cognitive decline in mouse models of AD. However, there is a knowledge gap on how and when neutrophils change and become activated, thus driving interactions with the microvasculature to cause neuroinflammation and cognitive impairment. We hypothesize that neutrophils become activated by hypoperfusion and AD pathology causing neutrophil- vascular dysfunction and neurodegeneration; this is likely exacerbated in mixed forms of AD. Aim1 will use longitudinal in vivo two-photon imaging to determine how and when neutrophils become reactive. We will also characterize cerebral blood flow, capillary stalling, neutrophil behavior, blood-brain barrier permeability, and vascular inflammation in a VCID, AD, and mixed AD mouse model. In Aim 2, we will utilize single-cell sequencing of neutrophils to determine whether certain neutrophils become more reactive in our disease models, and whether disease-associated neutrophil subpopulations drive disease progression. Furthermore, we will elucidate the molecular mechanisms that drive neutrophil changes, focusing on metabolism and glycosylation. Last, we will functionally test if neutrophils can be stopped from being activated and slow down disease progression. In summary, we will determine how hypoperfusion and AD pathology lead to changes in neutrophil reactivity and how such changes contribute to microvascular damage. We expect this work to lead to the identification of disease stage-specific biomarkers and shed light on the contribution of activated neutrophils to VCID and mixed AD.
