Microglia contributes to plaque growth by cell death due to uptake of amyloid ß in the brain of Alzheimer's disease mouse model.

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid ß (Aß) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aß plaques. The study of the brain of AD mouse models revealed that Aß plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aß plaque formation, growth and the mechanisms by which microglia contribute to Aß plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aß plaque formation and their growth in the brain of 5XFAD mice, the Aß-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 CX3CR1GFP/GFP mice. We found that activated microglia surrounding Aß plaques take up Aß, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aß into the extracellular space, which contributes to Aß 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 Aß plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.