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.

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.

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.

COVID-19 and Alzheimer’s disease:how one crisis worsens the other

Alzheimer’s disease(AD)has emerged as a key comorbidity of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).The morbidity and mortality of COVID-19 are elevated in AD due to multiple pathological changes in AD patients such as the excessive expression of viral receptor angiotensin converting enzyme 2 and pro-inflammatory molecules,various AD complications including diabetes,lifestyle alterations in AD,and drug-drug interactions.Meanwhile,COVID-19 has also been reported to cause various neurologic symptoms including cognitive impairment that may ultimately result in AD,probably through the invasion of SARS-CoV-2 into the central nervous system,COVID-19-induced inflammation,long-term hospitalization and delirium,and post-COVID-19 syndrome.In addition,the COVID-19 crisis also worsens behavioral symptoms in uninfected AD patients and poses new challenges for AD prevention.In this review,we first introduce the symptoms and pathogenesis of COVID-19 and AD.Next,we provide a comprehensive discussion on the aggravating effects of AD on COVID-19 and the underlying mechanisms from molecular to social levels.We also highlight the influence of COVID-19 on cognitive function,and propose possible routes of viral invasion into the brain and potential mechanisms underlying the COVID-19-induced cognitive impairment.Last,we summarize the negative impacts of COVID-19 pandemic on uninfected AD patients and dementia prevention.

Reprogrammed astrocytes display higher neurogenic competence, migration ability and cell death resistance than reprogrammed fibroblasts

The direct reprogramming of somatic cells into induced neural progenitor cells(iNPCs)has been envisioned as a promising approach to overcome ethical and clinical issues of pluripotent stem cell transplantation.We previously reported that astrocyte-derived induced pluripotent stem cells(iPSCs)have more tendencies for neuronal differentiation than fibroblast-derived iPSCs.However,the differences of neurogenic potential between astrocytederived iNPCs(AiNPCs)and iNPCs from non-neural origins,such as fibroblast-derived iNPCs(FiNPCs),and the underlying mechanisms remain unclear.Our results suggested that AiNPCs exhibited higher differentiation efficiency,mobility and survival capacities,compared to FiNPCs.The whole transcriptome analysis revealed higher activities of TGFβsignaling in AiNPCs,versus FiNPCs,following a similar trend between astrocytes and fibroblasts.The higher neurogenic competence,migration ability,and cell death resistance of AiNPCs could be abrogated using TGFβ signaling inhibitor LY2157299.Hence,our study demonstrates the difference between iNPCs generated from neural and non-neural cells,together with the underlying mechanisms,which,provides valuable information for donor cell selection in the reprogramming approach.

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.