Highlights d Ab induces metabolic reprogramming of microglia from OXPHOS to glycolysis d Metabolic reprogramming of microglia is dependent on the mTOR-HIF-1a pathway d Chronic exposure to Ab induces metabolic defects of microglia d Metabolic boosting with IFN-g restores immunological function of microglia

Natural inhibitors of Cas9 pretend to be DNA and block target binding, and using them in human cells can reduce off-target events.

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

Immune responses in the brain are thought to play a role in disorders of the central nervous system, but an understanding of the process underlying how immune cells get into the brain and their fate there remains unclear. In this study, we used a 2-photon microscopy to reveal that neutrophils infiltrate brain and migrate toward amyloid plaques in a mouse model of Alzheimer’s disease. These findings suggest a new molecular process underlying the pathophysiology of Alzheimer’s disease.