Myeloid Cells in Alzheimer's Disease: Culprits, Victims or Innocent Bystanders?

Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD.

TrendsMyeloid cells differ in their kinetics (long-lived versus short-lived) and localization. This should be taken into account when targeting myeloid cells during neurodegenerative diseases.Microglia are recruited to and cluster around newly formed Aβ plaques, indicating that they are not directly involved in the initial stages of amyloid plaque formation.Microglia are phagocytic cells in the brain equipped with several receptors that play a role in the clearance of Aβ. Downregulation of these immune-receptors results in compromised phagocytotic capacity of microglia.Morphological alterations such as dystrophic (senescent) microglia have been observed in the aged human and AD brain. Emerging data suggest that microglia deteriorate with age and are dysfunctional during AD.