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 co-ordinated 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 behavioural response following peripheral infection. With normal ageing, however, microglia develop a more inflammatory phenotype. For instance, in several models of ageing there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with ageing is referred to as primed, reactive or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in ageing has behavioural 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 with 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 behaviour, depressive-like behaviour 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.

Figure 1. Evidence of microglial priming in the aged brain

In normal aging there is increased mRNA and protein expression of several inflammatory markers on microglia. In older rodents and non-human primates these include proteins associated with antigen presentation, (MHC II and CD86), scavenger receptors (CD68), pattern associated recognition receptors (Toll-like receptors), and integrins (CD11b and CD11c). There are also detectable increases in inflammatory cytokines and decreases in anti-inflammatory cytokines in the aged brain. Last, in several aging models the morphology of the microglia is more de-ramifed. Collectively these findings are interpreted to indicate that microglia of the aged brain maintain a primed or activated immune profile.

Figure 2. Neurobehavioral complications associated with microglial reactivity in the brain of aged

Under normal conditions, microglia interpret and propagate inflammatory signals that are initiated either peripherally or centrally. Microglial activation increase cytokine and secondary messenger release that lead to transient physiological and behavioral responses that are beneficial to the host organism (top panel). A consequence of microglial priming with age, however, is a hyperactive response to an immune challenge with amplified and prolonged production of cytokines. In several models of aging, an exaggerated cytokine response is associated with the development of cognitive, behavioral, and physiological complications that are interpreted to be maladaptive to the host organism (bottom panel).

Figure 3. Activated microglia from the aged brain are refractory to anti-inflammatory stimulus

The activation of microglia is tightly regulated and there are several anti-inflammatory mediators that modulate microglial activation. For example, anti-inflammatory cytokines including IL-10, TGF-β, and IL-4 modulate the activation of microglia and are decreased in the brain with age. In addition neuronally derived ligands including CD200 and fractalkine (CX3CL1) are also decreased with age. The right panels depict the differences in expression of several regulatory proteins and receptors with age. There are also several regulatory systems in that the ligand and the receptor interaction that change when microglia become activated. For example, compared to adult microglia, aged microglia have prolonged reduction of CX3CR1 and fail to increase surface expression of the IL-4 receptor-α (bottom left panel). Taken together, the prolonged activation of microglia of the aged brain may be because they are less sensitive to the anti-inflammatory regulation that normally helps to resolve activation.