A growing body of evidence points to the inflammatory activity of microglia in the aging brain as an important contributing cause of neurodegenerative conditions. Some of these microglia have become senescent, and like other types of senescent cell, drive chronic inflammation and tissue dysfunction via the senescence-associated secretory phenotype (SASP). Others are merely activated, pushed into an inflammatory state by the presence of increasing levels of molecular waste and other forms of damage in brain tissue. Clearing out microglia and allowing them to repopulate has been shown to produce benefits in mice, as has the selective destruction of senescent microglia. This all points to inflammatory signaling as an important mechanism in age-related neurodegenerative conditions.
Microglia are immune cells of the brain, representing the neural tissue's defense system. A large body of evidence shows that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of Parkinson's disease (PD) patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, α-synuclein accumulation, and pro-inflammatory cytokine release.
In the central nervous system (CNS), microglia constitute up to 12% of all cells, and their density changes depending on the brain region. Early studies in mice showed that bone-marrow-derived hematopoietic cells move to the CNS, where they differentiate into microglia-like cells. With innovative conditional cell depletion techniques, it was recently shown that microglia have the ability to self-renew, and that interleukin-1 (IL-1) signaling is enabling this process.
Just like the abundance of microglia is region-specific, microglial morphology varies from brain area to brain area. In a resting state, microglia survey the brain microenvironment and show ramified morphology. Surveillance encompasses multiple functions: clearance of accumulated or deteriorated neuronal and tissue elements, dynamic interaction with neurons whilst regulating the synaptic pruning process, and maintaining overall brain homeostasis. Once activated upon brain damage and certain host or non-host stimuli, microglia are quickly undergoing a morphology change into an ameboid-like form, coupled with the release of inflammatory molecules, cytokines and chemokines. With regard to their activation, microglia are commonly divided into two classes: M1 (pro-inflammatory) or M2 (anti-inflammatory). Even though, by now, it is known that the states of activation are much more heterogeneous and diverse.
New approaches are being developed to determine sub-populations of microglia, mostly through single-cell gene expression studies and by determining fine morphological differences using computational methods. With age, microglia tend to express more IL-1β and they become more phagocytic in nature compared to microglia from younger brains. These phenotypic changes over time can influence their ability to function normally and attain the neuronal homeostasis and support. Eventually, an accumulation of non-functional, senescent microglia could contribute to irreversible and progressive neurodegeneration in PD.