In this proposal, we aim to dramatically improve the current microglial chemotactic model into a hybrid brain model that recapitulates pathological cascades of Alzheimer’s disease, including beta-amyloid deposits, microglial recruitment/clearance of beta-amyloid, neurofibrillary tangles and possibly neuronal death. To do this, we have been collaborating closely with Drs. Doo Yeon Kim and Rudolph E. Tanzi (Massachusetts General Hospital) to combine their novel “three-dimensional Alzheimer’s in a dish” model with our microglial chemotactic model. Drs. Kim’s and Tanzi’s 3-D AD human neurospheroid successfully recapitulates beta-amyloid and tau pathology in their system. By combining our microglia model and their 3-D AD neuron model, we can analyze the impact of human microglial cells on beta-amyloid and tau pathology. Furthermore, we can assess a hypothesis that human microglial cells are recruited to beta-amyloid deposits in a 3-D human neural culture model, and therefore contribute to AD pathogenesis.