Project Summary/Abstract Recent genetic and functional studies suggest microglia play a significant role in tau-associated neurodegeneration. However, key questions persist regarding microglia-neuron interactions in tau pathology and how diseased neurons affect microglial function. Recent research indicates neuronal electrophysiological defects, including alterations in oscillatory properties, can influence microglial transitions in Alzheimer's models. Our findings support widespread microglial changes early in tau pathology, including markers of synaptic regulation. We hypothesize that bidirectional changes between microglia and neurons in early tauopathy facilitate disease progression. To investigate, we propose a new model using microglial co-cultures with electrocompetent hippocampal assembloids derived from patient iPSC lines with MAPT mutations and controls, providing a foundation for exploring the maladaptive feedforward loop between microglia and early neuronal dysfunction in tau-related pathology.