Neuroinflammation is considered to play a crucial role in Alzheimer’s disease (AD) nowadays, placing glial cells on the front page. Although several evidences point to the decline of microglial defensive functions, the contribution of these cells in AD progression is still unknown. In recent years, microglial depletion approaches in mouse models have provided new insights into the role of these cells in physiological and pathological conditions (doi: 10.4103/1673-5374.308078). In this regard, our group has generated a genetic depletion AD model that allows the targeting of microglia in a cell-type specific and tamoxifen inducible fashion. At the same time, we have performed a pharmacological depletion treatment with identical animal ages and recovery times. In accordance with other reports, we observed that microglial depletion is followed by a rapid and complete repopulationa,b (doi:10.1016/j.nbd.2020.104956; doi: 10.3390/ijms22189734). Our results showed that these emerging microglia are less activated and seem to lose their ability to migrate and surround amyloid plaquesa,c. The consequences of this new microglial phenotype on the course of Alzheimer's disease are not yet known. Although we have not observed any differences in the amyloid loadc or the number of dystrophic neuritesh, preliminary behavioural tests and the analysis of synaptic proteins have shown a tendency for improvement in the cognitive decline of these AD micee,f,g. Our aim now is to shed some light on our understanding of microglia in a disease context and test whether microglial renewal strategies would be or not, a promising therapeutic strategy for neurodegenerative diseases.