Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models

- Manipulations of CSF1R signaling allow for research into microglial function in AD.
- Chronically activated microglia promote non-amyloid AD pathology.
- Peripheral myeloid cells are largely uninvolved in amyloid pathology maintenance.
- Targeting microglia-mediated effects may highlight key therapeutic avenues for AD.

Microglia are the primary immune cell of the brain and function to protect the central nervous system (CNS) from injury and invading pathogens. In the homeostatic brain, microglia serve to support neuronal health through synaptic pruning, promoting normal brain connectivity and development, and through release of neurotrophic factors, providing support for CNS integrity. However, recent evidence indicates that the homeostatic functioning of these cells is lost in neurodegenerative disease, including Alzheimer's disease (AD), ultimately contributing to a chronic neuroinflammatory environment in the brain. Importantly, the development of compounds and genetic models to ablate the microglial compartment has emerged as effective tools to further our understanding of microglial function in AD. Use of these models has identified roles of microglia in several pathological facets of AD, including tau propagation, synaptic stripping, neuronal loss, and cognitive decline. Although culminating evidence utilizing these microglial ablation models reports an absence of CNS-endogenous and peripheral myeloid cell involvement in Aβ phagocytosis, recent data indicates that targeting microglia-evoked neuroinflammation in AD may be essential for potential therapeutics. Therefore, identifying altered signaling pathways in the microglia-devoid brain may assist with the development of effective inflammation-based therapies in AD.