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The removal of dying neurons by microglia has a key role during both development and in several diseases. To date, little is known about the cellular and molecular processes underlying neuronal engulfment in the brain. Here we took a live imaging approach to quantify neuronal cell death progression in embryonic zebrafish brains and studied the response of microglia. We show that microglia engulf dying neurons by extending cellular branches that form phagosomes at their tips. At the molecular level we found that microglia lacking the phosphatidylserine receptors BAI1 and TIM-4, are able to recognize the apoptotic targets but display distinct clearance defects. Indeed, BAI1 controls the formation of phagosomes around dying neurons and cargo transport, whereas TIM-4 is required for phagosome stabilization. Using this single-cell resolution approach we established that it is the combined activity of BAI1 and TIM-4 that allows microglia to remove dying neurons. The removal of dying neurons by microglia plays a key role in both vertebrate nervous system development and several diseases. Here, the authors use a quantitative live imaging approach to investigate neuronal-microglial interactions at single-cell resolution and establish the functions of the phosphatidylserine receptors, TIM-4 and BAI1, in neuronal engulfment.

Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β‐peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor‐mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody‐mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 ( TREM2 ), a microglial gene involved in phagocytosis, were genetically linked to late onset AD. Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti‐Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose‐dependent manner in the presence or absence of TREM2. However, TREM2‐deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody‐bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies. Synopsis TREM2‐deficient phagocytic cells do not uptake antibody‐bound Aβ well, resulting in reduced clearance of amyloid plaques. This, however, can be compensated by elevated concentrations of immunotherapeutic antibodies, highlighting that monitoring microglia function in Alzheimer's disease is important. TREM2 deficiency reduces uptake of antibody‐bound Aβ by phagocytic cells. TREM2 deficiency lowers the efficacy of immunotherapeutic amyloid plaque clearance. Elevated anti‐Aβ antibody concentrations improve the phagocytic capacity of Trem2‐deficient cells. Graphical Abstract TREM2‐deficient phagocytic cells do not uptake antibody‐bound Aβ well, resulting in reduced clearance of amyloid plaques. This, however, can be compensated by elevated concentrations of immunotherapeutic antibodies, highlighting that monitoring microglia function in Alzheimer's disease is important.