Left: a schematic depiction of various strategies for targeting microglia and CNS-associated macrophages (CAMs) under homeostatic conditions. Both microglia and CAMs can be depleted using CSF1R inhibitors. Additionally, CAMs are effectively eliminated through clodronate liposome injections into the subarachnoid space. Replacement of these cells by blood-derived myeloid cells is another promising approach. While CAMs can be replaced through conventional bone marrow transplantation protocols, efficient replacement of microglia requires the use of CSF1R inhibition to create a niche for engrafting myeloid cells. These engrafted cells offer potential forex vivogene therapy, enabling autologous stem cell transplantation to introduce therapeutic genes into the CNS. Furthermore, recent advancements in adeno-associated virus (AAV9) vectors have allowed for more precise targeting of microglia. Right: targeting of microglia and CAMs during disease conditions. Microglia replacement has shown promise in treating microgliopathies, diseases caused by single-gene mutations resulting in microglial dysfunction and neurodegeneration (e.g., mutations inCSF1R,USP18, orTREM2). This approach could also be used to introduce therapeutic genes for other CNS cells, as demonstrated in lysosomal storage disorders (LSDs). In Alzheimers disease (AD), microglia engineered to express disease-modifying genes such asTREM2orAPOEcould be targeted to the CNS. Alternatively, microglia depletion in mice has been shown to alleviate amyloid pathology. By contrast, CAMs play a dual role in cerebral amyloid angiopathy (CAA): while they help clear beta-amyloid, they might also contribute to amyloid-driven cognitive decline. Replacing CAMs with CD36-deficient substitutes disrupts ROS generation, improving neurovascular function and cognitive outcomes.
