Targeting Microglia as a Treatment for Age-Related Neurodegeneration

Researchers here discuss some of the details involved in present efforts to adjust the behavior of inflammatory microglia in the aging brain. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. A sizable body of evidence implicates the ever more inflammatory activities of microglia in the onset and progression of neurodegenerative conditions. Innate immune cells react in this way to molecular signs of damage and cell stress produced by other aspects of aging, but when a state of inflammatory signaling persists for the long-term, it becomes harmful in and of itself, altering cell behavior for the worse throughout tissue, and producing dysfunction.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS.

Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress.

Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.