Review: Microglia of the aged brain: primed to be activated and resistant to regulation

Abstract

Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the coordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioral response following peripheral infection. With normal aging, however, microglia develop a more inflammatory phenotype. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with aging is referred to as primed, reactive, or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in aging has behavioral and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared to adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behavior, depressive-like behavior and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Several conditions of priming exist. For instance, aged rodents demonstrate increased expression of mRNA and protein markers of inflammation following LPS challenge (Kumar et al, 2013;Norden and Godbout, 2013;Norden et al, 2015aNorden et al, , 2015b. In addition to aging, similar priming effects have been reported in microglia from patients with neuropsychiatric disorders including traumatic brain injury (Fenn et al, 2014) and neurodegeneration (Norden et al, 2015a).…”

“…Astrocytes undergo phenotypic conversion during aging and can develop into the senescence-associated secretory phenotype (Salminen et al, 2011). This senescent phenotype exhibits exaggerated reactivity to immune activation and is associated with reduced glutamate clearance as well as the production of inflammatory cytokines (Haroon et al, 2015;Norden and Godbout, 2013).…”

Kinetic Modeling without Accounting for the Vascular Component Impairs the Quantification of [11C]PBR28 Brain PET Data

“…A recent study failed to demonstrate increased neuroinflammation with aging 10 despite the fact that microglial activation is an aging hallmark. 11 Another study demonstrated lack of microglial activity in patients with mild depression. 12 Although this particular depression phenotype might not have a neuroinflammatory component, TSPO binding was unexpectedly reduced in the depressed cohorts.…”

Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

“…Rather Gal-3+ staining may simply indicate that the microglial cell is Bprimed^for phagocytic activation while the presence of LN3+ staining may indicate the cell is Bprimed^for inflammatory activation (Norden and Godbout 2013;Perry and Holmes 2014). Double labeling with LN3 and Gal-3 would indicate that both processes are available when necessary.…”