摘要：Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.This has adverse motor and nonmotor effects,with the most prominent symptoms being tremors,rigidity,instability,and gait difficulties.While most patients have a late onset(60+years),certain dominant genetic mutations in the gene encoding α-syn are associated with earlier onset.Despite the severity and prevalence of the disease,no treatments that halt or modify the pathology progression exist,with available therapies providing only symptomatic relief for motor symptoms(Vázquez-Vélez and Zoghbi,2021).

摘要：Retinal ganglion cells are the bridging neurons between the eye and the central nervous system,transmitting visual signals to the brain.The injury and loss of retinal ganglion cells are the primary pathological changes in several retinal degenerative diseases,including glaucoma,ischemic optic neuropathy,diabetic neuropathy,and optic neuritis.In mammals,injured retinal ganglion cells lack regenerative capacity and undergo apoptotic cell death within a few days of injury.Additionally,these cells exhibit limited regenerative ability,ultimately contributing to vision impairment and potentially leading to blindness.Currently,the only effective clinical treatment for glaucoma is to prevent vision loss by lowering intraocular pressure through medications or surgery;however,this approach cannot halt the effect of retinal ganglion cell loss on visual function.This review comprehensively investigates the mechanisms underlying retinal ganglion cell degeneration in retinal degenerative diseases and further explores the current status and potential of cell replacement therapy for regenerating retinal ganglion cells.As our understanding of the complex processes involved in retinal ganglion cell degeneration deepens,we can explore new treatment strategies,such as cell transplantation,which may offer more effective ways to mitigate the effect of retinal degenerative diseases on vision.

摘要：The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipid-bilayer vesicles secreted by cells that play a crucial role in intercellular communication due to their diverse cargo.Among these,brain-derived extracellular vesicles,which are secreted by various brain cells such as neurons,glial cells,and Schwann cells,have garnered increasing attention.They serve as a promising tool for elucidating Parkinson's disease pathogenesis and for advancing diagnostic and therapeutic strategies.This review highlights the recent advancements in our understanding of brain-derived extracellular vesicles released into the blood and their role in the pathogenesis of Parkinson's disease,with specific emphasis on their involvement in the aggregation and spread of alpha-synuclein.Brain-derived extracellular vesicles contribute to disease progression through multiple mechanisms,including autophagy-lysosome dysfunction,neuroinflammation,and oxidative stress,collectively driving neurodegeneration in Parkinson's disease.Their application in Parkinson's disease diagnosis is a primary focus of this review.Recent studies have demonstrated that brain-derived extracellular vesicles can be isolated from peripheral blood samples,as they carry α-synuclein and other key biomarkers such as DJ-1 and various microRNAs.These findings highlight the potential of brain-derived extracellular vesicles,not only for the early diagnosis of Parkinson's disease but also for disease progression monitoring and differential diagnosis.Additionally,an overview of explorations into the potential therapeutic applications of brain-derived extracellular vesicles for Parkinson's disease is provided.Therapeutic strategies targeting brain-derived extracellular vesicles involve modulating the release and uptake of pathological alpha-synuclein-containing brain-derived extracellular vesicles to inhibit the spread of the protein.Moreover,brain-derived extracellular vesicles show immense promise as therapeutic delivery vehicles capable of transporting drugs into the central nervous system.Importantly,brain-derived extracellular vesicles also play a crucial role in neural regeneration by promoting neuronal protection,supporting axonal regeneration,and facilitating myelin repair,further enhancing their therapeutic potential in Parkinson's disease and other neurological disorders.Further clarification is needed of the methods for identifying and extracting brain-derived extracellular vesicles,and large-scale cohort studies are necessary to validate the accuracy and specificity of these biomarkers.Future research should focus on systematically elucidating the unique mechanistic roles of brain-derived extracellular vesicles,as well as their distinct advantages in the clinical translation of methods for early detection and therapeutic development.

摘要：The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.

摘要：Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain's borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.

摘要：Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia.The myelin sheath is a critical component of white matter,and damage and repair of the white matter are closely linked to myelin sheath integrity.This article reviews the role of microglia in vascular dementia,focusing on their effects on myelin sheaths and the potential therapeutic implications.The findings suggest that ischemia and hypoxia cause disruption of the blood-brain barrier and activate microglia,which may worsen blood-brain barrier damage through the release of matrix-degrading enzymes.Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation.Damage to the blood-brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia.Early activation of microglia is a protective response that contributes to the maintenance of blood-brain barrier integrity through sensing,debris-clearing,and defensive mechanisms.However,prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype,resulting in myelin damage and cognitive impairment.Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia,as both are closely linked to cognitive decline.Although effective clinical treatments for myelin damage in the central nervous system are currently lacking,researchers are actively working to develop targeted therapies.Several drugs,including nimodipine,dopaminergic agents,simvastatin,biotin,and quetiapine,have been evaluated for clinical use in treating microglial and myelin damage.Future research will face challenges in developing targeted therapeutic strategies for vascular dementia,requiring further investigation into the timing,duration,and specific mechanisms of microglial activation,as well as the exploration of new drug combinations and additional therapeutic targets.

摘要：Active inflammation in "inactive" progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis (PMS)has been framed as an inflammatory versus degenerative dichotomy.

摘要：The shared links between Alzheimer's disease and type 2 diabetes mellitus:Alzheimer's disease(AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that come with substantial daily struggles. Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression (Chen et al.,2022). Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD. Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.

摘要：Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson's disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson's disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormal α-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson's disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission of α-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson's disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson's disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson's disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson's disease.

摘要：Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS). This perspective introduces unconventional secretion pathways,focusing on secretory autophagy and its role in secreting protein aggregates associated with neurodegenerative disorders. We also explore additional neuronal functions of secretory autophagy beyond the release of protein aggregates. We propose autophagosomes as transport organelles that deliver cargo material directly from the endoplasmatic reticulum (ER) to the plasma membrane rather than solely to lysosomes.

摘要：Since the first electron micrograph of "lace-like structures" over 75 years ago,the endoplasmic reticulum (ER) is now viewed as a highly dynamic,constantly remodeling,continuous network of tubules and cisternae that plays an important role in a broad range of cellular activities from calcium regulation to protein synthesis and trafficking. In neurons,the ER extends from the soma through the axon to presynaptic terminals,and throughout the dendritic arbor into as many as half of all postsynaptic dendritic spines at any given time (Falahati et al.,2022). Dendritic spines are small protrusions decorating the branches of the dendritic arbor which receive most of the excitatory synaptic inputs in the central nervous system. Spines compartmentalize the postsynaptic mechanical and chemical responses tailored to the specific input that they receive. In addition to the wide range of shapes and sizes,spines also vary in their molecular and organellar composition,including ER. Recent findings reveal that neurons effectively exploit spine heterogeneity,particularly ER content to differentially tune spine function and structure during synaptic plasticity (Dittmer et al.,2024).

摘要：Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.

摘要：Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.

摘要：Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.

摘要：Parkinson's disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1(GLP-1)has beneficial effects in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation of α-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide,lipopolysaccharide binding protein,interleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson's disease.

摘要：Peripheral nerve injury causes severe neuroinflammation and has become a global medical challenge.Previous research has demonstrated that porcine decellularized nerve matrix hydrogel exhibits excellent biological properties and tissue specificity,highlighting its potential as a biomedical material for the repair of severe peripheral nerve injury;however,its role in modulating neuroinflammation post-peripheral nerve injury remains unknown.Here,we aimed to characterize the anti-inflammatory properties of porcine decellularized nerve matrix hydrogel and their underlying molecular mechanisms.Using peripheral nerve injury model rats treated with porcine decellularized nerve matrix hydrogel,we evaluated structural and functional recovery,macrophage phenotype alteration,specific cytokine expression,and changes in related signaling molecules in vivo.Similar parameters were evaluated in vitro using monocyte/macrophage cell lines stimulated with lipopolysaccharide and cultured on porcine decellularized nerve matrix hydrogel-coated plates in complete medium.These comprehensive analyses revealed that porcine decellularized nerve matrix hydrogel attenuated the activation of excessive inflammation at the early stage of peripheral nerve injury and increased the proportion of the M2 subtype in monocytes/macrophages.Additionally,porcine decellularized nerve matrix hydrogel negatively regulated the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB axis both in vivo and in vitro.Our findings suggest that the efficacious anti-inflammatory properties of porcine decellularized nerve matrix hydrogel induce M2 macrophage polarization via suppression of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway,providing new insights into the therapeutic mechanism of porcine decellularized nerve matrix hydrogel in peripheral nerve injury.

摘要：Microglia,the resident immune cells of the central nervous system,exhibit a wide array of functional states,even in their so-called "homeostatic"condition,when they are not actively responding to overt pathological stimuli. These functional states can be visualized using a combination of multi-omics techniques (e.g.,gene and protein expression,posttranslational modifications,mRNA profiling,and metabolomics),and,in the case of homeostatic microglia,are largely defined by the global (e.g.,genetic variations,organism's age,sex,circadian rhythms,and gut microbiota) as well as local (specific area of the brain,immediate microglial surrounding,neuron-glia interactions and synaptic density/activity) signals (Paolicelli et al.,2022). While phenomics (i.e.,ultrastructural microglial morphology and motility) is also one of the key microglial state-defining parameters,it is known that cells with similar morphology can belong to different functional states.

摘要：Ischemic stroke is a serious medical event that cannot be predicted in advance and can have long-lasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue.In recent years,research into regulatory long non-coding(lnc)RNAs,a diverse group of RNA molecules with regulatory functions,has emerged as a promising direction in the study of cerebral infarction.This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction,as well as potential strategies for their application in clinical settings.LncRNAs have the potential to act as"sponges"that attract specific microRNAs,thereby regulating the expression of microRNA target genes.These interactions influence various aspects of ischemic stroke,including reperfusion-induced damage,cell death,immune responses,autophagy,angiogenesis,and the generation of reactive oxygen species.We highlight several regulatory lncRNAs that have been utilized in animal model treatments,including lncRNA NKILA,lncRNA Meg8,and lncRNA H19.Additionally,we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction,such as lncRNA FOXO3,lncRNA XIST,and lncRNA RMST.The lncRNAs hold potential for genetic-level treatments in patients.However,numerous challenges,including inefficiency,low targeting accuracy,and side effects observed in preliminary studies,indicate the need for thorough investigation.The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.

摘要：Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson's disease(PD). Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss (Schon and Przedborski,2011). Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others. Active forms of caspase-8,-9 and-3,the ultimate executor apoptotic caspase,have also been detected in nigrostriatal dopaminergic neurons in the brains of PD patients. Therefore,a relevant question in the field is whether the blockage of the apoptotic pathway would be able to prevent cell death and become a therapeutical option for this disease.

摘要：Oligodendrocytes and their cell-intrinsic gene regulatory network:Oligodendrocytes (OLs) are the myelinating glial cells of the vertebrate central nervous system. They are responsible for insulating neuronal axons with a lipid-rich myelin sheath,which enables the saltatory conduction of action potentials.During development,oligodendrocyte progenitor cells (OPCs) emerge from neural stem cells in the ventricular zone. They then proliferate,increase their number,and migrate to their final destination where they encounter unmyelinated neuronal axons and differentiate in a stepwise fashion into myelinating oligodendrocytes (mOLs) under the influence of environmental stimuli.