Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP + /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

Nanoplastics (NPs) are ubiquitous environmental pollutants that have garnered considerable attention for their potential adverse health effects. In this study, male C57BL/6 J mice were orally treated with a mixture of 50-nm and 200-nm polystyrene (PS)-NPs for one week followed by measurements of their neurobehavioral performance and neuronal damage 10 months later. Notably, PS-NPs were detected in the brains of the mice by transmission electron microscopy (TEM) and a nanoscale hyperspectral microscope imaging system 10 months after the PS-NP exposure. The mice exposed to short-term PS-NPs exhibited cognitive dysfunction and anxiety-like symptoms, neuronal damage and synapse loss, and an increase in the number of M1-polarized microglia and A1-reactive astrocytes. Interestingly, the inhibition of microglial activation by minocycline significantly mitigated the PS-NP-induced synapse loss and neuron damage. In vitro studies showed that PS-NPs could be readily internalized by three types of neurovascular unit (NVU) cells, including microglia, astrocytes, and brain microvascular endothelial cells, via multiple pathways. RNA-seq analysis confirmed that microglia-mediated neuronal injury was associated with disturbances in synapse and cell death signaling pathways. Collectively, these findings suggest that short-term PS-NP exposure-induced neuroinflammation in early adulthood may not be resolved naturally but may deteriorate under the interaction of microglia and astrocytes, leading to synapse loss, neuron degeneration, and cognitive dysfunction in middle age. The results of the present study provide important insights into the potential neurological impacts of NPs and suggest that targeting microglia to suppress inflammation might be a potential intervention strategy for neurodegeneration induced by NPs.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by dopaminergic neuronal loss and chronic neuroinflammation, leading to significant motor and non-motor deficits. This study explores the therapeutic potential of alpha-linolenic acid (ALA), a known antioxidant and anti-inflammatory agent, in a lipopolysaccharide (LPS)-induced murine model of PD. Male Balb-C mice were divided into control, LPS-treated, LPS + ALA-treated and ALA-only groups. Behavioural assessments, including the pole test, rotarod test and open field test, revealed significant motor impairments in LPS-treated mice. Co-treatment with ALA partially ameliorated motor deficits in LPS-treated mice compared to the healthy control group. However, no direct comparison was made with standard PD treatments such as levodopa. Immunohistochemistry analysis showed a 68% reduction in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra pars compacta (SNpc) of LPS-treated mice. Notably, ALA co-treatment preserved dopaminergic neurons, demonstrating its neuroprotective effects. Western blotting and ELISA revealed heightened expression of inflammatory mediators, including TNF-α, IL-1β and NF-κB, in LPS-treated mice. ALA treatment significantly reduced these markers, indicating its capacity to mitigate neuroinflammation. Molecular docking analysis revealed moderate binding affinities of ALA to NF-κB (-5.1 kcal/mol), TNF-α (-5.7 kcal/mol) and IL-1β (-3.9 kcal/mol), suggesting possible interactions with key inflammatory pathways. These interactions were comparable to known inhibitors, indicating ALA's potential for neuroprotection. This study highlights the neuroprotective and anti-inflammatory effects of ALA in reducing dopaminergic neuronal loss and mitigating neuroinflammation in an LPS-induced PD model. Although behavioural improvements were moderate, these findings underscore ALA's potential as an adjunct therapeutic candidate for PD and other neurodegenerative diseases. Further research is warranted to explore its translational applications in clinical settings.

Multiple sclerosis (MS), as a primary cause of nontraumatic disability in young adults, has no effective treatment yet. Radix Rehmanniae (RR), a typical Traditional Chinese Medicine (TCM), is commonly used in MS patients as a most frequent herbal item in TCM formulas. Our recent study demonstrated that RR alleviated neurological deficits in an experimental MS model. However, direct evidence regarding the holistic mechanisms and bioactive components of RR for MS remains unclear. In this study, we employed an integrative strategy combining bioinformatics and experimental validation to profile the holistic mechanisms of RR, identify its bioactive components, and investigate their potential targets in MS. First, a network pharmacology approach was used to construct a "compound-target-pathway" network, indicating the action of RR on MS in a multicomponent-multitarget mode, and predicting Echinacoside and Acteoside as the primary bioactive ingredients. Bioinformatics analyses of transcriptomics and single-cell RNA sequencing based on GSE datasets indicated that oxidative stress and inflammatory/immune regulation in microglia might serve as crucial mechanisms of Echinacoside and Acteoside in MS pathology. Then, in vitro assays validated that Echinacoside and Acteoside possessed anti-inflammatory and antioxidant properties by scavenging ONOO- and H2O2 directly, and suppressing microglia-derived ONOO- production through inhibition of NF-κB-mediated iNOS and NADPH oxidase. In addition, molecular docking showed strong affinities between Acteoside and inflammation-related targets TGF-β and SMAD2. These findings provide the scientific evidence for clinical application of RR and bring novel insights into MS drug development.

After acute COVID-19, 5% of people experience persistent depressive symptoms and reduced cognitive function (COVID-DC). Theoretical models propose that astrogliosis is important in long COVID, but measures primarily indicative of astrogliosis have not been studied in the brain of long COVID or COVID-DC. The objective of the current study was to measure [11C]SL25.1188 total distribution volume ([11C]SL25.1188 VT), an index of monoamine oxidase B density and a marker of astrogliosis, with positron emission tomography in participants with COVID-DC and compare with healthy control participants.

In 21 COVID-DC cases and 21 healthy control participants, [11C]SL25.1188 VT was measured in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum. Depressive symptoms were measured with the Beck Depression Inventory-II, and cognitive symptoms were measured with neuropsychological tests.

[11C]SL25.1188 VT was higher in participants with COVID-DC in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum than in healthy control participants. Depressive symptom severity negatively correlated with [11C]SL25.1188 VT across prioritized brain regions. More recent acute COVID-19 positively correlated with [11C]SL25.1188 VT, reflecting higher values since predominance of the Omicron variant. Exploratory analyses found greater [11C]SL25.1188 VT in the hippocampus, dorsal putamen, and ventral striatum of COVID-DC participants than control participants with a major depressive episode with no history of COVID-19, and there was no relationship to cognitive testing in prioritized regions.

Results strongly support the presence of monoamine oxidase B-labeled astrogliosis in COVID-DC throughout the regions assessed, although the association of greater astrogliosis with fewer symptoms raises the possibility of a protective role. The magnitude of astrogliosis in COVID-DC is greater since the emergence of the Omicron variant.

In this study, the effect of crude polysaccharide (PF50) from the leaves of Perilla frutescens on the levels of inflammatory mediator proteins was evaluated through Western blotting and immunofluorescence analysis. The results showed that PF50 exerted potent anti-neuroinflammatory effects by significantly suppressing the NO release and expression of the proinflammatory cytokine mediators. Importantly, the PF50 concentration is independently protected against lipopolysaccharide (LPS)-triggered microglial activation-mediated neurotoxicity via inhibiting ROS production and improving mitochondrial function. To further investigate the active ingredients of PF50, a novel polysaccharide (PFP50-1) was purified and its anti-inflammatory activity was studied. PFP50-1 is composed of → 6) - β - D-Galp - (1 →, → 3,6) - α - D-Man p - (1 →, α - L-Araf - (1 →, → 4,6) - α-D-Glcp - (1 →, → 2,3,4) - α - L-Rhap - (1→ and β - D-Glcp - (1 →, which significantly reduced the abnormal elevation of proinflammatory cytokines in LPS-induced BV2 cells. Further experiments revealed that PFP50-1 inhibited the expression of proinflammatory mediator proteins including iNOS and COX-2. In summary, PFP50-1 has exhibited markedly anti-neuroinflammatory effects and may be one of the biologically active ingredients in PF50 for its anti-neuroinflammation and neuroprotection.

Microglial intrinsic immune checkpoints are essential safeguards to maintain immune homeostasis by preventing microglial overactivation, a process that substantially influences neurological disorders such as autism spectrum disorder (ASD). MEF2C is a crucial immune checkpoint that regulates microglial activation, but the mechanism remains unclear. We found that MEF2C-deficient (MEF2C-/-) induced microglia-like cells (iMGLs) derived from human pluripotent stem cells (hPSCs) exhibited overactivation following lipopolysaccharide stimulation, mimicking patterns observed in various neuroinflammatory disorders. High-throughput screening identified BMS265246, a cyclin-dependent kinase 2 (CDK2) inhibitor, which suppressed overactivation of MEF2C-/- iMGLs and normalized their inflammatory responses. Mechanistically, MEF2C transcriptionally upregulated p21 to inhibit CDK2 activation-mediated retinoblastoma protein (RB) degradation, thereby preventing transcription factor nuclear factor κB (NFκB) nuclear translocation and consequent microglial overactivation. BMS265246 treatment substantially ameliorated microglial overactivation and ASD-like behaviors in Mef2c-deficient mice. Our findings identify the MEF2C-p21-CDK2-RB-NFκB axis as a critical pathway to maintain microglial homeostasis and highlight CDK2 as a potential therapeutic target for neuroinflammation.

Reversing the decline of microglia in the dentate gyrus of stressed animals has antidepressant effects, but the molecular mechanisms are unclear. Since microglia normally interact with astrocytes and astrocytic purinergic 2Y1 receptor (P2Y1R) signaling plays an important role in regulating cellular crosstalk, we hypothesize that astrocytic P2Y1R signaling may mediate the antidepressant effects of microglia stimulation. Our results showed that a single injection of low-dose lipopolysaccharide (LPS) (100 μg/kg) elicited rapid antidepressant effects and a significant increase in adenosine triphosphate (ATP) levels in the dentate gyrus in chronically stressed mice, and that these effects of LPS were abolished by chemogenetic inhibition of microglia. Depletion of endogenous ATP, non-specific antagonization of purinergic receptors, or specific inhibition of P2Y1Rs, but not other purinergic receptors, by MRS2179 in the hippocampus abolished the antidepressant effects of low-dose LPS. Conditional gene knockout data showed that the antidepressant effect of low-dose LPS could not be observed in mice lacking P2Y1Rs in astrocytes but not in forebrain neurons. Chemogenetic inhibition of microglia in the dentate gyrus, specific deletion of P2Y1Rs in astrocytes and the absence of ATP abolished the increase in doublecortin (DCX)+ cells and brain-derived neurotrophic factor (BDNF) induced by a low dose of LPS in the dentate gyrus of stressed mice, and infusion of BDNF antibodies into the hippocampus simultaneously abolished the pro-neurogenesis and antidepressant effects of microglia stimulation in stressed mice. Taken together, these results suggest that ATP signaling mobilized by microglia stimulation has an antidepressant effect by triggering astrocytic P2Y1R-dependent synthesis of BDNF.

Ultra-high-risk state (UHR) concept was initially applied to promote the early detection of young help-seeking patients with higher risk of psychotic transition. However, most UHR individuals do not evolve to psychosis, stressing the need for biomarkers allowing the prediction of the transition. Substantial evidence suggest that redox dysregulation plays a major role in the pathophysiology of psychotic disorders. The aim of this study is to explore the relationship between the evolution of blood oxidative stress markers in UHR individuals. Blood samples were collected from 48 UHR individuals at their first visit and 12 months later for those who did not convert to psychosis (UHR-NC), or at the time of the transition for the converters (UHR-C). Markers for redox dysregulation, including the glutathione antioxidant system, superoxide dismutase, thioredoxin, TBARS, macrophage migration inhibitory factor, peroxiredoxin-4, MMP9 and sRAGE, were assessed in erythrocytes, serum and plasma. Statistical analyses revealed a combination of peripheral redox markers associated with the risk of transition to psychosis. These markers were able to discriminate between UHR-C and UHR-NC subjects at baseline. A decrease in blood levels of peroxiredoxin-4, an antioxidant enzyme, was associated with a lower risk of transition. GPx activity and TBARS levels were associated with the later severity of symptoms during the course of psychosis. These findings suggest the interest of peripheral biomarkers of oxidative stress to monitor the risk of psychosis. Overall, these findings hold promises for early detection and argue for the development of treatments targeting redox pathways in psychosis.

Neurodegenerative diseases (NDs) have caused serious health issues worldwide. A growing body of evidence suggests a correlation between neuroinflammation and abnormal microglial activity with ND symptoms. Microglia survey play crucial roles in CNS during health and the injury. It is proposed that sex affects microglial roles during inflammation, resulting in mouse behavioural changes and expression alterations in key markers related to microglia functions.

Male and female C57BL/6 mice were injected with a single dose of LPS (5 mg/kg, i.p.) or saline. After 48 h, an open field test was conducted, followed by brain tissues collection for measuring the expression of IGF-1, IL-1β and TREM2 and Immunohistochemistry (IHC) analysis for NLRP3 level.

Males displayed greater depressive-like behaviour in the OFT, with lower levels of IGF-1, IL-1β, and NLRP3 and high TREM2 expression. Female mice did not exhibit this behaviour, in contrast to male mice, they exhibited increased IL-1β and NLRP3 expression.

This study revealed that LPS-induced sex-specific changes in genes involved in neuronal cell survival caused behavioural alterations in male mice. Moreover, females had observed inflammatory responses that had no impact on behavioural alterations. Overall, both sexes exhibited sex-specific microglial activation states.

Nearly one billion individuals worldwide suffer from obstructive sleep apnea (OSA) and are potentially impacted by related neurodegeneration. TFEB is considered a master regulator of autophagy and lysosomal biogenesis, but little is known about its role in neuronal oxidative stress and resultant injury induced by OSA. This study aimed to investigate these issues. Here, we demonstrated that neuronal TFEB induction is repressed in OSA mouse models. Activation of a TFEB-dependent autophagy-lysosomal pathway (ALP) reduces hippocampal neuronal cell death and mitigates OSA-related cognitive impairment. Neuronal NRF2 induction was also found to be defective in OSA mouse models. A series of staining assays for HO1, SOD3, ROS, GSH, 8-OHdG, MDA and PI revealed that enhancement of NRF2 expression restores neuronal redox balance and protects hippocampal neurons. We then identified a novel interplay between TFEB-dependent ALP and NRF2-mediated relief of oxidative stress. Inhibition of NRF2 hinders TFEB expression and lysosomal biogenesis. Conversely, knockdown of TFEB or blocking autophagy dampens the antioxidative effect of NRF2. Our findings highlight the unexpected and crucial role of TFEB-dependent ALP as a downstream event of NRF2 in NRF2-promoted redox balance. This study provides novel insights into the mechanism behind NRF2-driven antioxidative action and the regulation of TFEB-dependent ALP.

Depression is a prevalent chronic psychiatric disorder with a growing impact on global health. Current treatments often fail to achieve full remission, highlighting the need for alternative therapeutic strategies. Mesenchymal stem cells (MSCs) have attracted significant interest for their therapeutic potential in neuropsychiatric disorders, primarily due to their capacity to target neuroinflammation. This study aimed to investigate if extracellular vesicles derived from human umbilical MSCs (hucMSCs) promote behavioral beneficial actions in a rat model of chronic unpredictable mild stress (CUMS). We show that a single dose of hucMSCs or their derived EVs (hucMSC-EVs) via the tail vein alleviated depressive-like behavior in rats, reduced markers of neuroinflammation, reduced pro-inflammatory cytokines (IL-1β and TNF-α), and increased the number and dendritic complexity of DCX-positive cells in the dentate gyrus. Proteomic analysis of EVs revealed the presence of proteins involved in modulation of inflammatory processes and cell activation. Our study demonstrates EVs derived from hucMSCs can effectively mitigate depressive symptoms by modulating neuroinflammatory pathways and enhancing neurogenesis. These findings support further exploration of MSC-derived EVs as a novel therapeutic option for neuropsychiatric disorders.

The presence of a neurogenic bladder is a severe but common complication of spinal cord injury (SCI). Multiple pathological factors, such as hypoxia, ischemia, and oxidative stress caused by SCI, promote M1 microglial polarization and the release of proinflammatory factors to amplify inflammation. An excessive inflammatory response stimulates the generation of reactive oxygen species (ROS) and induces oxidative stress to promote neuronal ferroptosis, thus leading to bladder dysfunction after SCI. Therefore, promoting the recovery of neural function by regulating the interaction between microglia and neurons is important. For this purpose, we developed an engineered immunoregulatory cyanobacterial capsule named siRNA@Cyanzyme, which consists of MnO2@zeolitic-imidazolate framework@cyanobacteria (Cyanzyme) and a small-interfering RNA targeting ACSL4 (siRNA-ACSL4). Cyanzyme reversed M1 microglial polarization via photosynthetic oxygen to promote anti-inflammatory factor release. MnO2 nanoenzymes grown on the surface of ZIF-8 eliminated excessive ROS to reduce oxidative stress. Moreover, Cyanzyme increased the delivery efficiency of siRNA-ACSL4, which is a key regulator of ferroptosis. Both treatments alleviated GABAergic neuron damage to mitigate bladder dysfunction. Our data demonstrated that siRNA@Cyanzyme effectively reversed M1 microglial polarization, reduced neuronal ferroptosis, and ultimately restored neurogenic bladder function.

Neuroinflammation generally refers to an inflammatory response within the central nervous system caused by various pathological insults, including infection, trauma, ischemia, and toxins. As the brain's sentinel immune cell, microglia are tasked as the first responders to infection or tissue injury and initiating an inflammatory response. The perennial shrub plant Rosmarinus officinalis L. was reported to possess anti-inflammatory, anticancer, anti-nociceptive, antidiabetic, neuroprotective, and antioxidative properties. The present study aimed to investigate the effects of Rosmarinus officinalis ethanolic extracts on the lipopolysaccharide (LPS)-induced neuroinflammation model of BV-2 cells in comparison to carnosol and carnosic acid, phenolic diterpenes of the plant. Ultrasound-assisted extraction was used to have ethanolic extract of the plant. LPS was used to induce inflammation in BV-2 cells. Tumor necrosis alpha (TNF-α), interleukin 1 beta (IL-1β) secretion, reactive oxygen species (ROS) production, GSH/GSSG ratio, protein carbonyl level, and caspase-3 activity were evaluated. Inflammation induced by LPS was reduced by the ethanolic extract. Both carnosol and carnosic acid decreased the TNF-α and IL-1β levels as well. The ethanolic extract reduced ROS production and protein carbonylation, and increased GSH/GSSG ratio more effectively compared to the effects of carnosol and carnosic acid. Results depicted that caspase-3 activity was reduced by the ethanolic extract and this effect was more pronounced compared to carnosol and carnosic acid. The present study indicates the ethanolic extract of Rosmarinus officinalis rescues BV-2 cells from apoptosis via alleviating inflammation and oxidative stress.

Hypertension-related Depression (HD) is a complex mental disorder that exerts a significant negative impact on patients' quality of life. Previous studies have demonstrated that damages to vascular endothelial and hippocampus are the primary pathological features in HD rats. Under hypertensive conditions, inflammatory cytokines in peripheral blood vessels can induce central nervous system inflammation through penetration of a damaged blood-brain barrier, peripheral immune cells, and neural pathways, damaging the brain and triggering HD. Therefore, interactions between vascular endothelial cells, neurons, and glial cells are critical for the understanding of HD. However, in vivo animal models are often limited by the complexity of intrinsic systems, high inter-individual variability, and stringent ethical regulations. A reliable model that could be easily manipulated is needed for investigating the mechanisms involved in communication between vascular endothelial cells, neurons, and glial cells in HD. We therefore aimed to create a composite tri-culture model consisting of rat aortic endothelial cells (RAECs), neurons, and microglia to study HD. First, RAECs were stimulated with lipopolysaccharide to mimic endothelial injury under hypertensive conditions. Vascular endothelial function and inflammatory levels were assessed using fluorescent probes and enzyme-linked immunosorbent assays. RAECs treated with 1 μg/ml LPS for 24 h had reduced levels of nitric oxide, increased levels of endothelin-1 and inflammatory mediators. These findings are consistent with the endothelial dysfunction and inflammatory responses observed in spontaneously hypertensive rats, which suggests that the lipopolysaccharide-induced RAECs model effectively mimics key pathological features of hypertension-related endothelial injury. Subsequently, the supernatants from lipopolysaccharide-induced RAECs were combined with 200 μM corticosterone and transferred to neuron-microglia co-cultures to simulate damages to hippocampal neuron under HD conditions. To evaluate the features of cells, neuronal viability was measured by CCK-8 and live-dead assays. Nissl staining was used to assess neuronal Nissl bodies, while the levels of inflammatory factors and monoamine neurotransmitters in the culture supernatants were evaluated by enzyme-linked immunosorbent assays. Reactive oxygen species in neurons were visualized by a fluorescent probe, apoptosis was detected using TUNEL assays, and immunofluorescence was used to assess microglial phenotypes and the levels of TLR4 and NF-κB. It was found that neurons in the tri-culture model had reduced viability, higher levels of apoptosis, fewer Nissl bodies, increased inflammation, and reduced levels of monoamine neurotransmitters. Additionally, the number of M1 microglia was increased, along with elevated levels of TLR4 and NF-κB proteins. These findings were similar to damages of hippocampal neuron, abnormal levels of monoamine neurotransmitters, microglia polarization, and hippocampal inflammatory response observed in the HD rat model. In conclusion, our findings indicate that the tri-culture model can effectively simulate the pathological characteristics of HD, especially in vascular endothelial damage, neuroinflammation, monoamine neurotransmitters disorders. Therefore, the tri-culture model would provides a reliable and invaluable experimental tool for further research on the pathogenesis and treatment of HD.

Metabolic disorders and brain insulin resistance (IR) are major risk factors for the development of neurodegenerative conditions. Kumquat fruit (KF) administration has demonstrated significant anti-dysmetabolic effects, improving peripheral IR in murine models of metabolic syndrome. Along these lines, this study evaluated the neuroprotective effects of KF supplementation in a model of dysmetabolism-induced neuronal damage and its ability to counteract the disruption of brain insulin signalling. To this end, biochemical and histological analysis assessed neuroapoptosis, disruption of brain insulin signalling and neuroinflammation in a model of high-fat diet (HFD)-induced neuronal damage. Our findings demonstrate, for the first time, that KF supplementation significantly counteracts HFD-induced neuroapoptosis downregulating pro-apoptotic genes (FAS-L, BIM and P27) and upregulating the anti-apoptotic ones (BDNF and BCL-2). Coherently, KF positively influenced the expression of selected genes related to Alzheimer's Disease. Relevantly, these effects were associated to KF ability to restore brain insulin signalling by increasing insulin receptor expression, reducing IRS-1 serine phosphorylation, enhancing both AKT activation and GSK-3β inactivation. Accordingly, KF suppressed HFD-neuroinflammation, counteracting the overexpression of NF-κB and its downstream enzymatic products, iNOS and COX-2. Collectively, these findings demonstrate the neuroprotective benefits of KF administration, supporting its potential as a dietary intervention for dysmetabolic-related neurodegenerative disorders.

Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management.

This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ1-42 oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes.

Injection of Aβ1-42 oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons.

Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.

Hypobaric hypoxia is widely recognized as a prominent risk factor for high-altitude cerebral edema (HACE), which contributes to the exacerbation of multiple pathological mechanisms, including oxidative stress, mitochondrial dysfunction, disruption of blood-;brain barrier integrity, neuroinflammation, and neuronal apoptosis. Among these mechanisms, abnormalities in oxygen metabolism, including hypoxia, oxidative stress, and mitochondrial dysfunction, play pivotal roles in the pathophysiology of HACE. In this review, our objective is to enhance our comprehension of the underlying molecular mechanisms implicated in HACE by investigating the potential involvement of oxygen metabolism. Addressing aberrations in oxygen metabolism holds promise for providing innovative therapeutic strategies for managing HACE.

Parkinson's disease (PD) is a widespread neurodegenerative disorder characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). This review aims to summarize the recent advancements in the pathophysiological mechanisms of pyroptosis, mediated by NLRP3 inflammasome, in advancing PD and the anti-pyroptotic agents that target NLRP3 inflammatory pathways and miRNA. PD pathophysiology is primarily linked to the aggregation of α-synuclein, the overproduction of reactive oxygen species (ROS), and the development of neuroinflammation due to microglial activation. Prior research indicated that a significant quantity of microglia is activated in both PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models, triggering neuroinflammation and resulting in a cascade of cellular death. Microglia possess an inflammatory complex pathway termed the nucleotide-binding oligomerization domain-, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome. Activation of the NLRP-3 inflammasome results in innate cytokines maturation, including IL-18 and IL-1β, which initiates the neuroinflammatory signal and induces a type of inflammatory cell death known as pyroptosis. Upon neuronal damage, intracellular levels of damage-associated molecular patterns (DAMPs), including reactive oxygen species (ROS), would build. DAMPs induce unregulated cell death and subsequent release of oxidative intermediates and pro-inflammatory cytokines, leading to the progression of PD. Thus, targeting of neuroinflammation using antipyroptotic medications can be efficiently achieved by blocking NLRP3 and obstructing IL-1β signaling and release. Furthermore, many research studies showed that miRNAs have been identified as regulators of the NLRP3 inflammasome and Nrf2 signal, which subsequently modulate the NLRP3-Nrf2 axis in PD. Nanotechnology promises potential for the advancement of miRNA-based therapies. Nanoparticles that ensure miRNA stability, traverse the blood-brain barrier (BBB) and distribute miRNA targeting regions needed to be created. In conclusion, targeting the pyroptosis pathway via NLRP3 or miRNA may serve as a prospective therapeutic strategy for PD in the future.

Implanted neural interfaces are electronic devices that stimulate or record from neurons with the purpose of improving the quality of life of people who suffer from neural injury or disease. Devices have been designed to interact with neurons throughout the body to treat a growing variety of conditions. The development and use of implanted neural interfaces is increasing steadily and has shown great success, with implants lasting for years to decades and improving the health and quality of life of many patient populations. Despite these successes, implanted neural interfaces face a multitude of challenges to remain effective for the lifetime of their users. The devices are comprised of several electronic and mechanical components that each may be susceptible to failure. Furthermore, implanted neural interfaces, like any foreign body, will evoke an immune response. The immune response will differ for implants in the central nervous system and peripheral nervous system, as well as over time, ultimately resulting in encapsulation of the device. This review describes the challenges faced by developers of neural interface systems, particularly devices already in use in humans. The mechanical and technological failure modes of each component of an implant system is described. The acute and chronic reactions to devices in the peripheral and central nervous system and how they affect system performance are depicted. Further, physical challenges such as micro and macro movements are reviewed. The clinical implications of device failures are summarized and a guide for determining the severity of complication was developed and provided. Common methods to diagnose and examine mechanical, technological, and biological failure modes at various stages of development and testing are outlined, with an emphasis on chronic in vivo characterization of implant systems. Finally, this review concludes with an overview of some of the innovative solutions developed to reduce or resolve the challenges faced by implanted neural interface systems.

Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.

Traumatic brain injury (TBI) disrupts oxygen homeostasis in the brain, leading to excessive reactive oxygen species (ROS) production and dysregulated antioxidant mechanisms, which fail to clear excess ROS. This ROS overload promotes the expression of pro-inflammatory genes, releasing cytokines and chemokines and creating a vicious "ROS-neuroinflammation" cycle, making it essential to break this cycle for effective TBI treatment. In this study, we developed cysteine-alanine-glutamine-lysine (CAQK) peptide-modified antioxidant nanoparticles (C-PPS/C) for co-delivery of curcumin (Cur) to modulate oxidative and neuroinflammatory disturbances after TBI. In TBI mice, C-PPS/C nanoparticles accumulated in injured brain regions, where poly (propylene sulfide)120 scavenged ROS, reducing oxidative stress, while Cur release further suppressed ROS and inflammation. C-PPS/C nanoparticles broke the "ROS-neuroinflammation" cycle, protecting the blood-brain barrier (BBB), reducing acute brain edema, and promoting long-term neurological recovery. Further investigation showed that C-PPS/C nanoparticles inhibited the NF-κB pathway, reducing pro-inflammatory gene expression and mitigating inflammation, suggesting a promising approach for TBI treatment.

Pharmacological treatment of epilepsy presents several challenges, particularly the ineffectiveness of antiseizure medicines (ASMs) in modifying disease. In fact, the removal of reactive oxygen species (ROS) and preconditioning with tolerable dose of nitric oxide (NO) can activate neuroprotective mechanisms during latency and enhance tolerance to oxidative stress during seizures. To address this, a ROS-responsive cascade Nano-formulation (RRCN) is developed, which will transform ROS into NO. Remarkably, RRCN significantly reduces seizure severity, prolongs seizure latency, and extends inter-seizure intervals, though it does not increase the latency of generalized seizures. Microglia, the primary immune cells of the brain, play a crucial role in the initiation and progression of epilepsy. In the kainic acid (KA) epilepsy model, microglial processes elongate, branching increases, and interactions between microglia and neurons are strengthened in the CA1 and CA3 regions of the hippocampus compared to the Vehicle group. RRCN reverses these dynamic changes in microglia and their interactions with neurons, which are mediated by the NO/HIF/ErBb2 pathway. Thus, RRCN can inhibit seizures generalization by preconditioning the dynamic changes of microglia.

Low-intensity pulsed ultrasound (LIPUS) is a promising modality for neuromodulation. Microglia are the resident immune cells in the brain and their mobility is critical for maintaining brain homeostasis and alleviating neuroimmune pathologies. However, it is unclear whether and how LIPUS modulates microglial migration in physiological conditions.

Here we examined the in vitro effects of LIPUS on the mobility of BV2 microglia by live cell imaging. Single-cell tracing of BV2 microglia migration was analyzed using ImageJ and Chemotaxis and Migration Tool software. Pharmacological manipulation was performed to determine the key molecular players involved in regulating ultrasound-dependent microglia migration.

We found that the distance of microglial migration was enhanced by LIPUS with increasing acoustic pressure. Removing the extracellular Ca2+ influx or depletion of intracellular Ca2+ stores suppressed ultrasound-enhanced BV2 migration. Furthermore, we found that blocking the reorganization of actin, or suppressing purinergic signaling by application of apyrase or hemi-channel inhibitors, both diminished ultrasound-induced BV2 migration. LIPUS stimulation also enhanced microglial migration in a lipopolysaccharide (LPS)-induced inflammatory environment.

LIPUS promoted microglia migration in both physiological and inflammatory environments. Calcium, cytoskeleton, and purinergic signaling were involved in regulating ultrasound-dependent microglial mobility. Our study reveals the biomechanical impact of ultrasound on microglial migration and highlights the potential of using ultrasound-based tools for modulation of microglial function.

Schisandrachinensis, a traditional functional Chinese medicine, is known for its ability to tonify the kidneys, calm the heart, and tranquilize the mind. Recent pharmacological research has demonstrated its anti-inflammatory and neuroprotective effects.

We had previously demonstrated that Schisandra chinensis lignans (SCL) promote microglia polarization to M2 phenotype via targeting cannabinoid receptor type-2 (CB2R) to exert antidepressant effects. Considering the pathological features of abnormal microglial phagocytosis in chronic unpredictable mild stress (CUMS)-induced depression model, the current study aimed to build relationship between microglial phagocytosis and phenotype, further to explore whether SCL exerts antidepression by ameliorating abnormal phagocytotic "stressed-but-viable" neuron by targeting microglial CB2R.

Endocannabinoid levels were analyzed using Triple Quadrupole LC/MS. In vivo immunofluorescence assay was employed to evaluate the microglial abnormal phagocytosis. Then, we build models which one was microglia BV2 phagocytized FITC-IgG conjugated latex beads, the other was BV2 co-cultured with stressed-but-viable neurons. Phagocytosis was quantified using flow cytometry. The expression of calreticulin (CRT) in total, intracellular, and surface fractions was validated by Western blot, flow cytometry, and immunofluorescence. The other proteins, such as LRP1, microglial phenotype markers and the PERK-eIF2α pathway, were assessed by Western blot. The qRT-PCR was used to evaluate microglial phenotype markers. Based on the interaction between endocannabinoids and SCL with CB2R, we conducted a CB2R pharmacological antagonist in the CUMS model and used siRNA against CB2R in BV2 cells to verify the findings.

SCL improved the disrupted levels of endocannabinoids induced by CUMS. In vivo studies revealed that the CB2R antagonist AM630 reversed the SCL-reduced efficiency of microglial mistakenly phagocytosed stressed-but-viable neurons and the up-regulated level of M2 phenotype. In the in vitro studies, we identified SCL activated M2 microglia via CB2R targeting, leading to a reduction in the neuronal cell-surface CRT, inhibition of the "eat-me" signaling, and alleviation abnormal phagocytosis. In-depth investigation performed in the co-culture model revealed that this mechanism involved the inactivation of the PERK-eIF2α pathway in neuronal cells by M2 microglia to exert the above-mentioned effects.

Overall, the improved abnormal phagocytotic process appears to be influenced by SCL and endocannabinoids, promoting microglial polarization toward the M2 phenotype in a CB2R-dependent manner. Specifically, this mechanism involves M2 microglia inactivation of the PERK-eIF2α pathway in stressed-but-viable neurons, thereby reducing CRT translocation to the cell surface and enhancing the regulation of abnormal phagocytosis, ultimately contributing to an antidepressant effect.

Gait impairment is closely related to quality of life in patients with Parkinson's disease (PD). This study aimed to explore alterations in brain microstructure in PD patients and healthy controls (HCs) and to identify the correlation of gait impairment in the ON and OFF states of patients with PD, respectively.

We enrolled 24 PD patients and 29 healthy controls (HCs) from the Movement Disorders Program at Beijing Friendship Hospital Capital Medical University between 2019 and 2020. We acquired magnetic resonance imaging (MRI) scans and processed the diffusion kurtosis imaging (DKI) images. Preprocessing of diffusion-weighted data was performed with Mrtrix3 software, using a directional distribution function to track participants' main white matter fiber bundles. Demographic and clinical characteristics were recorded. Quantitative gait and clinical scales were used to assess the status of medication ON and OFF in PD patients.

The axial kurtosis (AK), mean kurtosis (MK), and radial kurtosis (RK) of five specific white matter fiber tracts, the bilateral corticospinal tract, left superior longitudinal fasciculus, left anterior thalamic radiation, forceps minor, and forceps major were significantly higher in PD patients compared to HCs. Additionally, the MK values were negatively correlated with Timed Up and Go Test (TUG) scores in both the ON and OFF in PD patients. Within the PD group, higher AK, MK, and RK values, whether the patients were ON or OFF, were associated with better gait performance (i.e., higher velocity and stride length).

PD exhibits characteristic regional patterns of white matter microstructural degradation. Correlations between objective gait parameters and DKI values suggest that dopamine-responsive gait function depends on preserved white matter microstructure. DKI-based Tract-Based Spatial Statistics (TBSS) analysis may serve as a tool for evaluating PD-related motor impairments (e.g., gait abnormalities) and could yield potential neuroimaging biomarkers.

Recent research underscores the cerebellum's growing importance in forensic science and neurology, showing its functions extend beyond motor control, especially in identifying causes of death. Critical neuropathological markers including alpha-synuclein and tau protein aggregates, cellular degeneration, inflammation, and vascular changes are vital for identifying neurodegenerative diseases, injuries, and toxic exposures. Advanced forensic methods, such as Magnetic resonance imaging (MRI), immunohistochemistry, and molecular analysis, have greatly improved the accuracy of diagnoses. Promising new therapies, including neuroprotective agents like resveratrol and transcranial magnetic stimulation (TMS), offer potential in treating cerebellar disorders. The cerebellum's vulnerability to toxins, drugs, and traumatic brain injuries (TBIs) highlights its forensic relevance. Moreover, advancements in genetic diagnostics, such as next-generation sequencing and CRISPR-Cas9, are enhancing the understanding and treatment of genetic conditions like Joubert syndrome and Dandy-Walker malformation. These findings emphasize the need for further research into cerebellar function and its broader significance in both forensic science and neurology.

Microglia function as a vital constituent in the maintenance of brain homeostasis. Aberrant microglial activation, however, may contribute to neurodegenerative diseases. Lithospermic acid (LA) is a plant-derived polycyclic phenolic carboxylic acid isolated from Salvia miltiorrhiza. The present study investigated the potential effects of lithospermic acid on LPS-induced neuroinflammation in BV2 microglial cells and determined the mechanism of action of this compound. Cells were pre-treated with lithospermic acid for 1 h and incubated with LPS for 24 h. qPCR, immunofluorescence, and immunoblot assays were used to determine the expression of iNOS, COX2, NF-κB p65, and HSP90 expression. ELISA was employed to measure the production of pro-inflammatory cytokines. Lithospermic acid dramatically reduced LPS-stimulated cell migration and decreased NF-κB p65 nuclear translocation. Furthermore, lithospermic acid also markedly decreased the production of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α in a dose-dependent manner. Additionally, lithospermic acid inhibited NO and PGE2 production in response to LPS, and it also inhibited the expression of iNOS and COX2 in a dose-dependent manner. Molecular docking and experimental verification have demonstrated that lithospermic acid inhibits the activity and expression of HSP90. Small interfering RNA knockdown of HSP90 expression, which abrogated LPS-induced inflammation. These findings suggest that the lithospermic acid targeting HSP90 attenuates LPS-induced inflammatory response via the NF-κB signalling pathway in BV2 microglial cells. Collectively, lithospermic acid may offer therapeutic benefits for neurodegenerative disorders associated with microglial activation and could serve as a potential inhibitor/agent for the treatment of neuroinflammation.

The aim of this study is to investigate whether arginine and its metabolites can be an endophenotype for bipolar disorder (BD) and to evaluate the role of arginine metabolites and neurocognitive function levels in unaffected healthy children of parents diagnosed with BD in cognitive impairment.

The study included 37 healthy children of parents diagnosed with BD Type I as the high-risk group and 36 healthy children of parents without any psychiatric disorders as the control group. The arginine, n-monomethyl-l-arginine acetate (L-NMMA), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), citrulline, homoarginine, ornithine serum levels, and nitric oxide synthase (NOS) activity level of both groups were compared.

The study found that in the high-risk group, ADMA, SDMA, and ornithine levels were significantly higher compared to the controls, while citrulline and NOS activity level were significantly lower in the high-risk group compared to the controls. All neurocognitive performances of the high-risk group were considered statistically significantly worse compared to controls. The impairment in neurocognitive functions in the high-risk group was found to be correlated with ADMA, L-NMMA, citrulline, homoarginine, ornithine levels, and NOS activity level.

These findings highlight a potential link between arginine metabolism and executive dysfunction in individuals at high risk for BD. Further longitudinal studies are essential to fully understand the complex interactions between these factors.

Cardiac arrest (CA) is one of the most common illnesses worldwide. Post-CA brain injury (PCABI) is a major cause of death and poor recovery in CA patients and the current CA treatments are not very effective. The microbiome-gut-brain axis has been found to significantly affect brain ischemia injury. Furthermore, in ischemic stroke patients, short-chain fatty acids (SCFA), especially sodium butyrate (SB), have been observed to promote neuroprotective effects by modulating inflammatory response and microglial polarization in the cortex. However, the precise mechanism of SB on CA-induced injury remains elusive. Therefore, this research study established an oxygen-glucose deprivation and reoxygenation (OGD/R) model using BV-2 microglial and HT22 cells to simulate cerebral ischemia/reperfusion injury in vitro and a potassium chloride-induced CA mouse model to mimic CA in vivo. The data revealed that SB markedly improved neurological scores and reduced neuronal death and apoptosis. Moreover, it reduced M1 microglia and neuroinflammation in CA mice. In addition, SB increased intestinal integrity and alleviated systemic inflammation. The 16S rDNA sequencing analysis indicated that SB intervention mitigated CA-induced gut microbiota dysbiosis and SCFA depletion. It was also observed that CA mice's brain and OGD/R-exposed BV2 cells had substantially increased levels of MyD88, phosphorylated NF-κB p65, and TLR4 proteins, which were reduced after SB treatment. In summary, this study revealed that SB can protect against cerebral ischemia-reperfusion injury by controlling microglia polarization and microbiome-gut-brain axis to inhibit brain inflammation via the TLR4/MyD88/NF-κB pathway.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.

Microglia serve as vital innate immune cells in the central nervous system, playing crucial roles in the generation and development of brain neurons, as well as mediating a series of immune and inflammatory responses. The morphologic transitions of microglia are closely linked to their function. With the advent of single-cell sequencing technology, the diversity of microglial subtypes is increasingly recognized. The intricate interactions between microglia and neuronal networks have significant implications for psychiatric disorders and neurodegenerative diseases. A deeper investigation of microglia in neurologic diseases such as Alzheimer disease, depression, and epilepsy can provide valuable insights in understanding the pathogenesis of diseases and exploring novel therapeutic strategies, thereby addressing issues related to central nervous system disorders.

Brain aging is the leading risk factor for most neurodegenerative diseases and has been linked with high rates of neuron loss. Thus, identifying molecular mechanisms underlying neuron loss and pharmacological modulation may be of great importance for slowing or preventing age-related diseases. Herein, we investigated the roles of miR-92a, Akt, mTOR, and NF-κB in age-associated apoptosis in the hippocampus (a critical structure involved in brain aging) of male rats alone and in combination with prazosin. Twenty-four male Wistar rats were grouped into young control (3-month-old), aged (18-month-old), and aged + prazosin groups (n = 8 for each). Prazosin (1 mg/kg; i.p.) was administered for 4 weeks to aged rats. Apoptosis was detected by TUNEL staining. Western blot for Akt, mTOR, and NF-κB was conducted. miR-92a gene expression was performed by using RT-PCR. The results indicated a marked enhancement of apoptosis in the aging hippocampus. We also detected substantial up-regulation of NF-κB as well as substantial down-regulation of phosphorylated-Akt and mTOR in the aging hippocampus. Moreover, miR-92a gene expression was markedly reduced in the aging hippocampus. Treatment with prazosin significantly suppressed apoptosis and reversed miR-92a gene expression, as well as Akt, mTOR, and NF-κB protein expressions in the aging hippocampus. Considering the NF-κB regulatory role on miRNAs, our results suggest that NF-κB may be a negative transcriptional regulator of miR-92a, which in turn could regulate the Akt/mTOR signaling. In this regard, NF-κB upregulation may mediate the downregulation of miR-92a/Akt/mTOR axis, and thereby contribute to age-related neurodegeneration. This may provide a novel treatment target for delaying or preventing age-related problems.

Engineered extracellular vesicles play an increasingly important role in the treatment of spinal cord injury. In order to prepare more effective engineered extracellular vesicles, we biologically modified M2 microglia. Angiopep-2 (Ang2) is an oligopeptide that can target the blood-brain barrier. Through single-cell sequencing and immunofluorescence experiments, we confirmed that the expression of LRP-1, the targeted receptor of Ang2, was elevated after spinal cord injury. Subsequently, we integrated the Ang2 peptide segment into M2 microglia to obtain Ang2-EVs, which could successfully target the site of spinal cord injury. However, in order to improve the function of Ang2-EVs, we pretreated M2 microglia with melatonin, which has anti-inflammatory effects, to obtain M-Ang2-EVs. The results of single-nucleus sequencing of the mouse spinal cord verified that neurons and OPCs gradually transformed into subtypes related to nerve repair functions after treatment with M-Ang2-EVs. This is consistent with the sequencing and enrichment analysis of miRNAs contained in M-Ang2-EVs. We further verified through experiments that M-Ang2-EVs can promote microglia/macrophages to phagocytose sphingomyelin, promote axon remyelination and axon elongation, and maintain the integrity of the blood-spinal barrier. Since Ang2 can also target the blood-brain barrier, we found that M-Ang2-EVs can also reduce brain inflammation that results from spinal cord injury. Our study applied the Angiopep-2 peptide to spinal cord injury to enhance the targeting of injured cells, and successfully construct engineered extracellular vesicles that can target the spinal cord injury site and the brain.

Sleep behavior is regulated by diverse mechanisms including genetics, neuromodulation and environmental signals. However, it remains completely unknown regarding the roles of epitranscriptomics in regulating sleep behavior. In the present study, we showed that the deficiency of RNA m6A methyltransferase Mettl3 in excitatory neurons specifically induces microglia activation, neuroinflammation and neuronal loss in thalamus of mice. Mettl3 deficiency remarkably disrupts sleep rhythm and reduces the amount of non-rapid eye movement sleep. We also showed that Mettl3 regulates neuropeptide Y (NPY) via m6A modification and Mettl3 conditional knockout (cKO) mice displayed significantly decreased expression of NPY in thalamus. In addition, the dynamic distribution pattern of NPY is observed during wake-sleep cycle in cKO mice. Ectopic expression of Mettl3 and NPY significantly inhibits microglia activation and neuronal loss in thalamus, and restores the disrupted sleep behavior of cKO mice. Collectively, our study has revealed the critical function of Mettl3-m6A-NPY axis in regulating sleep behavior.

As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.