Project 460535

Late-onset Alzheimer's disease (LOAD), which occurs after the age of 65 and comprises most cases of Alzheimer's disease involves progressive memory loss and neuronal cell death in the brain. As current approaches towards comprehending Alzheimer's have not yet stopped the disease, therefore, recent efforts have encouraged understanding other main contributors in Alzheimer's. The goal of this proposal is to demonstrate how dark microglia, a particular microglial state active in eating neurons could underlie clinical LOAD progression. Although meant to contain stressed neurons, ingesting neurons with tau aggregates may cause these dark microglia to become impaired. These impaired, dark microglia likely fail to break down protein aggregates and act as further hotspots to amplify tau pathology. If my hypothesis is supported, dark and impaired microglia critically accelerate the disease's pace and could explain the progressive memory loss in LOAD. Dark microglia have been observed in disease mouse models and aged human brains, but not yet in LOAD patients. Thus, LOAD patient and control samples will be collected and novelly assessed for dark and/or impaired microglia using three-dimensional electron microscopy over two years. Cutting-edge imaging methods will be used to measure how impaired dark microglia may relate to other Alzheimer's pathologies (e.g., tau protein aggregates). Impaired dark microglia are predicted to increase in patient versus control brains, and to localize near and/or contain protein aggregates involved in LOAD. If these predictions are confirmed, showing that the abundance of dark and/or impaired microglia correlates with LOAD would increase priority for investigating their usefulness as therapeutic targets.