Impact of Aging in Microglia-Mediated D-Serine Balance in the CNS

Abstract

A mild chronic inflammatory state, like that observed in aged individuals, affects microglial function, inducing a dysfunctional phenotype that potentiates neuroinflammation and cytotoxicity instead of neuroprotection in response to additional challenges. Given that inflammatory activation of microglia promotes increased release of D-serine, we postulate that age-dependent inflammatory brain environment leads to microglia-mediated changes on the D-serine-regulated glutamatergic transmission. Furthermore, D-serine dysregulation, in addition to affecting synaptogenesis and synaptic plasticity, appears also to potentiate NMDAR-dependent excitotoxicity, promoting neurodegeneration and cognitive impairment. D-serine dysregulation promoted by microglia could have a role in age-related cognitive impairment and in the induction and progression of neurodegenerative processes like Alzheimer's disease.

Figure 1

D-serine synthesis and degradation. D-serine is synthetized by isomerization of L-serine in a reaction catalyzed by the enzyme serine racemase which, in addition, also catalyzes the α,β-elimination of water from L-serine or D-serine to produce pyruvate and ammonia. Although serine racemase also has the potential to degrade D-serine through α,β-elimination of water, it is preferentially degraded through oxidation by the enzyme D-amino acid oxidase, generating hydroxypyruvate, peroxide, and ammonia.

Figure 2

Impact of aging in microglial function and release of D-serine. In aging, a mild chronic inflammation promotes dysfunction of microglia and their cytotoxic activation. In contrast to young microglia, aged microglia show changes in TGFβ1-Smad signaling that promote an inflammatory microglial phenotype. They release decreased levels of anti-inflammatory cytokines and high levels of proinflammatory cytokines and D-serine. The inflammatory environment together with increased levels of free D-serine could induce impairment in synaptogenesis and synaptic plasticity and contribute to neurodegeneration.