Age- and Sex-Specific Regulation of Serine Racemase in the Retina of an Alzheimer's Disease Mouse.

Purpose: Changes associated with Alzheimer's disease (AD) may have measurable effects on the retina, which may facilitate early detection due to the eye's accessibility. Retinal pathology and the regulation of serine racemase (SR) were investigated in the retinas of APP(SW)/PS1(∆E9) mice.

Methods: SR in the retinas and the content of D-serine in the aqueous humor were analyzed.

Effects of Topic Delivery of an Inhibitor of Serine Racemase on Laser-Induced Choroidal Vasculopathy.

Purpose: Intravitreal injection of anti-VEGF antibodies remains the primary therapy for exudative age-related macular degeneration (exAMD), although its efficacy is limited. Previous research has demonstrated that both a loss-of-function mutation of srr and the intravenous injection of a serine racemase inhibitor, L-aspartic acid β-hydroxamate (L-ABH), significantly inhibit laser-induced choroidal neovascularization (CNV) in mice. Given that L-ABH is a small molecule, this study investigated the effects of L-ABH administered via eye drops on CNV, aiming to develop a noninvasive treatment strategy for exAMD.

Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs.

Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans.

Alterations of serine racemase expression determine proliferation and differentiation of neuroblastoma cells.

Although the role of serine racemase (SR) in neuropsychiatric disorders has been extensively studied, its role in cell proliferation and differentiation remains unclear. Deletion of Srr, the encoding gene for SR, has been shown to reduce dendritic arborization and dendritic spine density in the brains of adult mice, whereas increased SR levels have been associated with differentiation in cell cultures. Previously, we demonstrated that valproic acid induces differentiation in the N2A neuroblastoma cell line, and that this differentiation is associated with increased SR expression.

Serine Racemase Expression Differentiates Aging from Alzheimer's Brain.

Aging is an inevitable process characterized by progressive loss of physiological integrity and increased susceptibility to cancer, diabetes, cardiovascular, and neurodegenerative diseases; aging is the primary risk factor for Alzheimer's disease (AD), the most common cause of dementia. AD is characterized by brain pathology, including extracellular deposition of amyloid aggregation and intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition, losses of synapses and a wide range of neurons are pivotal pathologies in the AD brain.

Deletion of serine racemase reverses neuronal insulin signaling inhibition by amyloid-β oligomers.

Dysregulation of insulin signaling in the Alzheimer's disease (AD) brain has been extensively reported. Serine racemase (SR) modulates insulin secretion in pancreatic islets. This study aimed to examine whether SR regulates insulin synthesis and secretion in neurons, thereby modulating insulin signaling in the AD brain.

Amyloid peptide exerts a rapid induction of Dicer1 protein in neuron via reducing phosphorylation.

A growing number of evidence suggests that altered microRNA network in the brain contributes to the risk of Alzheimer's disease(AD). Dicer1 is a type III riboendonuclease which cleaves pre-microRNA into functional microRNA. Reduction of Dicer1 or Dicer1 mutation has been involved in cancer, aging or age-related macular degeneration.

Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling.

Neovascular age-related macular degeneration (neoAMD) is the leading cause of blindness in AMD and manifests as choroidal neovascularization (CNV). Anti-vascular endothelial growth factor (VEGF) therapies are the mainstay treatments but with limited efficacy and cause detrimental effects on the retina after long-term application. These disadvantages warrant alternative strategy.

Impairment of Store-operated Calcium Entry: Implications in Alzheimer's Neurodegeneration.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder. Dysfunction of central cholinergic neurons, amyloid aggregation and deposition,oxidative stress,and biometal dyshomeostasis has been regarded as the major pathogenic mediators in this devastating disease. However, strategies derived from these hypotheses fail to slow down or stop the progression of AD, warranting a combination of therapies to target multiple etiological factors or examining alternative hypothesis.

Overexpression of D-amino acid oxidase prevents retinal neurovascular pathologies in diabetic rats.

Aims/hypothesis: Diabetic retinopathy is characterised by retinal neurodegeneration and retinal vascular abnormalities, affecting one third of diabetic patients with disease duration of more than 10 years. Accumulated evidence suggests that serine racemase (SR) and D-serine are correlated with the pathogenesis of diabetic retinopathy and the deletion of the Srr gene reverses neurovascular pathologies in diabetic mice. Since D-serine content is balanced by SR synthesis and D-amino acid oxidase (DAAO) degradation, we examined the roles of DAAO in diabetic retinopathy and further explored relevant therapy.

Dicer1 promotes Aβ clearance via blocking B2 RNA-mediated repression of apolipoprotein E.

Metabolism of β-amyloid is critical for healthy brain. Decreased clearance of β-amyloid is associated with ensued accumulation of amyloid peptide, culminating in formation of senile plaques, a neuropathological hallmark of Alzheimer's disease(AD). Apolipoprotein E (APOE), a lipoprotein for phospholipid and cholesterol metabolism, is predominantly synthesized by glia in the central nervous system, controlling Aβ aggregation and metabolism.

Brain Dicer1 Is Down-Regulated in a Mouse Model of Alzheimer's Disease Via Aβ42-Induced Repression of Nuclear Factor Erythroid 2-Related Factor 2.

Dicer1 is a microRNA-processing enzyme which plays critical roles in neuronal survival and neuritogenesis. Dicer1 deletion induces neurodegeneration or degeneration in retinal pigment epithelium, which is associated with oxidative stress. Oxidative stress is thought to be central in the pathogenesis of Alzheimer's disease (AD).

Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid.

Serine racemase (SR) synthesizes l-type serine to its enantimor, d-serine which participates in physiological processes and in pathological conditions. In the central nervous system, SR is highly expressed in neurons and astrocytes but expressed at relatively lower amount in microglia. However, the mechanism by which SR is highly expessed in neurons is hitherto unknown.

Autophagic degradation of stromal interaction molecule 2 mediates disruption of neuronal dendrites by endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress has been highlighted as one of the factors involved in axon/dendrite degeneration, which is an early event in Alzheimer's, Parkinson's diseases as well as in acute disorders such as ischemia and axotomy-induced retinal ganglion cell degeneration. These lines of evidence suggest critical roles of ER stress at the early stage of neurodegeneration, but the relevant mechanism is rarely exploited. In this study, we report that treatment with sublethal level of ER stressors, tunicamycin or brefeldin A, in primary rat neuronal cultures, significantly reduced dendrite arbor.

Intravenous injection of l-aspartic acid β-hydroxamate attenuates choroidal neovascularization via anti-VEGF and anti-inflammation.

Choroidal neovascularization (CNV) is a hallmark of exudative age-related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti-VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti-VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l-Aspartic acid β-hydroxamate (L-ABH), significantly reduced CNV at the dose 6 mg/kg on the first day before and followed by 3 mg/kg on the third day after laser injury.

MicroRNA-29 enhances autophagy and cleanses exogenous mutant αB-crystallin in retinal pigment epithelial cells.

Retinal pigment epithelial cells (RPEs), a pigmented cell layer in the outer retina, are constantly exposed to photo-oxidative stress. Autophagy relieves the stress by removing oxidative protein adducts, protein aggregates, and damaged mitochondria. We previously found that miR-29 is downregulated in choroid/RPE tissue in a model of exudative age-related macular degeneration (AMD), suggesting that miR-29 deficiency may contribute to autophagy inhibition and AMD progression.

Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice.

Consistent results suggest the promoting roles of serine racemase (SR)/D-serine in retinal neurodegeneration in diabetic retinopathy (DR). However, the direct evidence connecting SR deficiency with retinal neuroprotection in genetic model of diabetes mellitus has not been reported. In this investigation, we explore the effect of absence of functional SR on the degeneration of retinal ganglion cells (RGCs) with a diabetic murine model, Ins2 mice.

Potential deficit from decreased cerebellar granule cell migration in serine racemase-deficient mice is reversed by increased expression of GluN2B and elevated levels of NMDAR agonists.

Inward migration of cerebellar granule cells (CGCs) after birth is critical for lamination in the cerebellar cortex. N-methyl-d-aspartate (NMDA) subtype of glutamate receptor (NMDAR) tethering CGCs into Bergmann glial fibers mediates the inward movement during the glial-dependent migratory phase. Activation of NMDAR depends on simultaneous binding of the GluN2 subunit by glutamate, and of the GluN1 subunit by d-serine or glycine; d-serine is believed to be an endogenous ligand of NMDAR.

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells.

Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor.

Disrupted-in-schizophrenia-1 as a broader link of glutamatergic transmission to schizophrenia impacts cerebral neurochemistry via the production of the 'gliotransmitter' d-serine, a NMDA receptor coagonist.

This Editorial highlights a study by Xia and coworkers in the current issue of the Journal of Neurochemistry, in which the authors reveal a possible mechanistic link between DISC1 (disrupted-in-schizophrenia-1), a genetic risk factor for schizophrenia, and N-methyl-d-aspartate receptor (NMDAR) that is also linked with schizophrenia. The authors show that perturbed communication between DISC1 and NMDARs represents a hidden perpetrator for abnormal dendritic and synaptic maturation. Read the highlighted article 'DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders' on page 518.

Inhibition of store-operated calcium entry by sub-lethal levels of proteasome inhibition is associated with STIM1/STIM2 degradation.

Dysfunction of the ubiquitin-proteasome system (UPS) and calcium homeostasis has been implicated in the neurodegeneration of Alzheimer's and Parkinson's diseases. The cytosolic calcium concentration is maintained by store-operated calcium entry (SOCE), which is repressed by Alzheimer's disease-associated mutants, such as mutant presenilins. We hypothesized that inhibition of UPS impacts SOCE.