Microglia Contributes to Plaque Growth by Cell Death Due to Uptake of Amyloid β in the Brain of Alzheimer's Disease Mouse Model

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid beta (A beta) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding A beta plaques. The study of the brain of AD mouse models revealed that A beta plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of A beta plaque formation, growth and the mechanisms by which microglia contribute to A beta plaque formation are unknown. In the present study, we confirmed how microglia are involved in A beta plaque formation and their growth in the brain of 5XFAD mice, the A beta-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1(GFP/GFP) mice. We found that activated microglia surrounding A beta plaques take up A beta, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated A beta into the extracellular space, which contributes to A beta plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of A beta plaques by causing microglial cell death in the brain.