Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer’s disease

The central nervous system (CNS) is endowed with its own resident innate immune cells, the microglia. They constitute approximately 10% of the total cells within the CNS parenchyma and act as ‘sentinels’, sensing and mitigating any deviation from homeostasis. Nevertheless, under severe acute or chronic neurological injury or disease, microglia are unable to contain the damage, and the reparative activity of monocyte-derived macrophages (MDMs) is required. The failure of the microglia under such conditions could be an outcome of their prolonged exposure to hostile stimuli, leading to their exhaustion or senescence. Here, we describe the conditions under which the microglia fall short, focusing mainly on the context of Alzheimer’s disease, and shed light on the functions performed by MDMs. We discuss whether and how MDMs engage in cross-talk with the microglia, why their recruitment is often inadequate, and potential ways to augment their homing to the brain in a well-controlled manner.