Microglial glutaminase 1 mediates chronic restraint stress-induced depression-like behaviors and synaptic damages

Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely unknown.Recently,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.

Neural stem cell-derived extracellular vesicles mitigate Alzheimer’s disease-like phenotypes in a preclinical mouse model

Dear Editor,Alzheimer’s disease(AD)is the most common neurodegenerative disorder and the No.1 cause of dementia in elderly with no effective treatments.1 The application of stem cell-derived extracellular vesicles(EVs)has emerged as a promising therapeutic strategy for AD.2 EVs are small bilipid layer-enclosed vesicles that display blood-brain barrier(BBB)penetrating ability and similar potency to their parental cells.

Reprogrammed mouse astrocytes retain a“memory”of tissue origin and possess more tendencies for neuronal differentiation than reprogrammed mouse embryonic fibroblasts

Direct reprogramming of a variety of somatic cells with the transcription factors Oct4(also called Pou5f1),Sox2 with either Klf4 and Myc or Lin28 and Nanog generates the induced pluripotent stem cells(iPSCs)with marker similarity to embryonic stem cells.However,the difference between iPSCs derived from different origins is unclear.In this study,we hypothesized that reprogrammed cells retain a“memory”of their origins and possess additional potential of related tissue differentiation.We reprogrammed primary mouse astrocytes via ectopic retroviral expression of OCT3/4,Sox2,Klf4 and Myc and found the iPSCs from mouse astrocytes expressed stem cell markers and formed teratomas in SCID mice containing derivatives of all three germ layers similar to mouse embryonic stem cells besides semblable morphologies.To test our hypothesis,we compared embryonic bodies(EBs)formation and neuronal differentiation between iPSCs from mouse embryonic fibroblasts(MEFsiPSCs)and iPSCs from mouse astrocytes(mAsiPSCs).We found that mAsiPSCs grew slower and possessed more potential for neuronal differentiation compared to MEFsiPSCs.Our results suggest that mAsiPSCs retain a“memory”of the central nervous system,which confers additional potential upon neuronal differentiation.

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons

Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPSCs,reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.Methods:Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors(TFs)Foxg1,Sox2,and Brn2.The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a.Results:Astrocyte-derived induced NPCs(AiNPCs)share high similarities,including the expression of NPC-specific genes,DNA methylation patterns,the ability to proliferate and differentiate,with the wild type NPCs.The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes.Interestingly,additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation,respectively.Conclusions:Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs.Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.

Proteolytic processing of SDF-1α by matrix metalloproteinase-2 impairs CXCR4 signaling and reduces neural progenitor cell migration

Neural stem cells and neural progenitor cells(NPCs)exist throughout life and are mobilized to replace neurons,astrocytes and oligodendrocytes after injury.Str-omal cell-derived factor 1(SDF-1,now named CXCL12)and its receptor CXCR4,an α-chemokine receptor,are critical for NPC migration into damaged areas of the brain.Our previous studies demonstrated that immune activated and/or HIV-1-infected human monocyte-derived-macrophages(MDMs)induced a substantial increase of SDF-1 production by human astrocytes.However,matrix metalloproteinase(MMP)-2,a protein up-regulated in HIV-1-infected macrophages,is able to cleave four amino acids from the N-terminus of SDF-1,resulting in a truncated SDF-1(5-67).In this study,we investigate the diverse signaling and function induced by SDF-1α and SDF-1(5-67)in human cortical NPCs.SDF-1(5-67)was generated by incubating human recombinant SDF-1α with MMP-2 followed by protein determination via mass spectrometry,Western blotting and ELISA.SDF-1α induced time-dependent phosphorylation of extracellular signal-regulated kinases(ERK)1/2,Akt-1,and diminished cyclic adenosine monophosphate(cAMP).In contrast,SDF-1(5-67)failed to induce these signaling.SDF-1α activation of CXCR4 induced migration of NPCs,an effect that is dependent on ERK1/2 and Akt-1 pathways;whereas SDF-1(5-67)failed to induce NPC migration.This observation provides evidence that MMP-2 may affect NPC migration through post-translational processing of SDF-1α.

Extracellular vesicles,from the pathogenesis to the therapy of neurodegenerative diseases

Extracellular vesicles(EVs)are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells.Being a key intercellular communicator,EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases(NDs)including Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease through delivery of bioactive cargos within the central nervous system(CNS).Importantly,CNS cell-derived EVs can be purified via immunoprecipitation,and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs.Given the essential impact of EVs on the pathogenesis of NDs,pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs.In this review,we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs,summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs,and comprehensively discuss promising potential of EVs as therapeutic targets,agents,and drug delivery systems in treating NDs,together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.

Translational Neurodegeneration in the era of fast growing international brain research

Another year has flown by and we have entered 2022.The challenges in 2021 have continued to occur as we unceasingly fight against the pandemic.2021 will be remembered for the world’s perseverance and dedication to overcome extremely adverse circumstances.At the beginning of 2022,we are celebrating the 10th birthday of our journal,Translational Neurodegeneration(TN).Inaugurated in 2011 under the editorship and leader-ship of Dr.Shengdi Chen,our mission is to promote and foster rapid conversion of basic science research to clinical applications by offering a high-visibility forum for groundbreaking translational research in neurodegenera-tive diseases and to ultimately benefit not only patients but also societies.

Emerging roles of extracellular vesicles in mediating RNA virus infection

The sudden outbreak of COVID-19 has once again shrouded people in the enormous threat of RNA virus.Extracellular vesicles(EVs),eukaryotic cells-derived small bi-layer vesicles mainly consisting of exosomes and microvesicles,share many properties with RNA viruses including structure,size,generation,and uptake.Emerging evidence has implicated the involvement of EVs in the pathogenesis of infectious diseases induced by RNA viruses.EVs can transfer viral receptors(e.g.,ACE 2 and CD9)to recipient cells to facilitate viral infection,directiy transport infectious viral particles to adjacent cells for virus spreading,and mask viruses with a host structure to escape immune surveillance.Here,w e examine the current status of EVs to summarize their roles in mediating RNA virus infection,together with a comprehensive discussion of the underlying mechanisms.