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.

Silica-Coated Magnetic Nanoparticles Activate Microglia and Induce Neurotoxic D-Serine Secretion

“…We observed intracellular granular structure formation and increment of d-Serine secretion in MNPs@SiO 2 (RITC)-treated microglia. d-Serine secretion in microglia responds to amyloid beta, LPS, and secreted amyloid precursor protein [35,36], but d-serine secretion in NP-treated microglia had not been reported. Concomitant with the increase in d-serine secretion, gene expression related to the transport of serine family amino acids was increased as indicated by combined transcriptome and amino acid pro ling analyses.…”

“…We observed intracellular granular structure formation and increment of d-Serine secretion in MNPs@SiO 2 (RITC)-treated microglia. d-Serine secretion in microglia responds to amyloid beta, LPS, and secreted amyloid precursor protein [35,36] [36,37]. Moreover, although we have previously observed excitotoxic glutamate production in MNPs@SiO 2 (RITC)-treated HEK293 cells based on metabotranscriptome analysis [26], the mechanisms of d-serine production and secretion in MNPs@SiO 2 (RITC)-treated microglia have not been unraveled.…”

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

“…Serine, specifically D-serine, is thought to be a critical excitatory neurotransmitter acting as a co-agonist of the N-methyl D-aspartate (NMDA) receptor on neurons, and depletion due to deficient synthesis or racemase activity likely leads to catastrophic neurotoxicity [ 96 ]. Abnormal D-serine levels in the brain are thought to contribute to neurodegenerative disorders such as Alzheimer’s disease and schizophrenia [ 97 , 98 , 99 , 100 ]. Expression of serine biosynthesis enzymes are highly regulated by several factors, including NRF2-ATF4 [ 101 , 102 ], c-Myc [ 103 ], and hypoxia inducible factors [ 104 ].…”

Advances in D-Amino Acids in Neurological Research

“…This is important because it has recently been shown that D-serine levels are significantly lower in humans suffering from Schizophrenia, probably caused by blunted expression of serine racemase and overexpression of DAAO [ 114 ]. D-Serine plays a role in the onset of Alzheimer’s Disease and dementias [ 33 , 43 , 47 , 120 ]. Indeed, overexpression of D-serine in the brain appears to be a contributing cause of Alzheimer’s Disease [ 33 , 43 ].…”

“…Indeed, overexpression of D-serine in the brain appears to be a contributing cause of Alzheimer’s Disease [ 33 , 43 ]. It has been suggested that D-serine is released by astrocytes due to inflammation and leading to neurotoxicity in early Alzheimer’s Disease patients [ 43 , 48 , 120 ]. It has also known that the increased levels of D-serine within astrocytes come from an overexpression of Serine Racemase, which suggests a novel potential drug target for fighting Alzheimer’s Disease [ 48 ].…”