Brain Microvascular Pericyte Pathologies in Alzheimer's Disease and Diabetes 5 views

The brain depends on a continuous, precisely regulated blood supply delivered through its microvasculature, and vascular impairments are among the earliest detectable changes in Alzheimer's Disease (AD). Diabetes is strongly associated with elevated AD risk and shares overlapping microvascular pathologies with AD, yet the cellular mechanisms underlying their potential connection remain poorly understood. This dissertation argues that brain capillary pericytes are active contributors to neurovascular dysfunction in both contexts, developing that argument across two methodologically independent approaches. Using a 14-day streptozotocin mouse model of early hyperglycemia and longitudinal two-photon microscopy, pericytes were shown to uncouple from capillaries across multiple brain regions, most prominently in the entorhinal cortex and hippocampus. Pericytes were also shown to constrict capillaries in proportion to fasting glucose levels, reducing red blood cell velocity before pericyte loss occurs. Constricting and uncoupling pericytes represented behaviorally distinct states. In human postmortem AD tissue, single-nucleus RNA sequencing and intercellular communication modeling identified sex- and region-specific disruptions in pericyte signaling. Female AD donors showed increased pericyte-to-endothelial TGFβ activation and reduced pericyte-astrocyte estrogen-associated signaling in the middle temporal gyrus. A conserved microglia-to-pericyte inflammatory program was identified across brain regions in both sexes. These two methodologically independent approaches converge on pericyte pathology as an active feature of disease. One approach captures its early temporal emergence in the living diabetic brain; the other reveals its molecular and signaling dimensions in human AD tissue. Together, these approaches constitute the dissertation's central contribution.

PHD (Doctor of Philosophy)

2026-06-12