NeuroMolecular Medicine最新文献

Alzheimer's disease is a multifaceted neurodegenerative condition marked by the build-up of amyloid plaques and neurofibrillary tangles that lead to progressive cognitive impairment. Neuroinflammation, especially the activation of microglia, plays a pivotal part in driving this pathology. Microglia are the brain's resident immune cells and can adopt a spectrum of activation states that support either neuroprotection or neurodegeneration. Evidence shows that their phenotypes are highly dynamic and shaped by environmental influences and pathological signals. During the early phases of the disease, microglia tend to assume anti-inflammatory roles that facilitate plaque clearance and promote tissue recovery. Prolonged or dysregulated activation, however, shifts them toward a pro-inflammatory state that amplifies neuronal damage. Several molecular pathways including JAK STAT, PI3K AKT, and MAPK are central to regulating these processes and have emerged as promising therapeutic targets. This review summarizes current insights into microglial phenotypic transitions, the signaling mechanisms governing their activation, and the therapeutic potential of modulating neuroinflammation. Enhancing the neuroprotective capacity of microglia, suppressing chronic inflammatory responses, and targeting key receptors such as TREM2 and P2 × 7 represent potential strategies. A deeper understanding of microglial interactions with other glial cells and the molecular drivers of their activation may provide new avenues for slowing or halting the progression of Alzheimer's disease and related neurodegenerative disorders.

Sepsis-associated encephalopathy (SAE) is a serious sepsis complication with high mortality. Animal models, including cecal ligation and puncture (CLP), lipopolysaccharide (LPS) injection, and peritoneal contamination and infection (PCI), are known to trigger distinct inflammatory responses with differential hippocampal impact. This study aimed to comprehensively compare the hippocampal transcriptomic profiles and validate key findings through independent experimentation. Transcriptomic datasets GSE253309 (CLP), GSE226120 (LPS), and GSE167610 (PCI) were retrieved from the GEO database. Bioinformatics analyses were employed to identify DEGs and enriched pathways. WGCNA pinpointed characteristic modules, and PPI networks were constructed and analyzed. Critically, an independent CLP-induced SAE mouse model was established, and hippocampal RNA sequencing was performed for confirmation. DEG analysis revealed 381, 533, and 85 significant DEGs in the CLP, LPS, and PCI datasets, respectively. CLP and LPS models shared a robust signature of neuroinflammation, significantly enriching GO terms related to immune response and inflammatory response, and KEGG pathways such as TNF, NF-κB, IL-17. In stark contrast, the PCI model was predominantly associated with cell migration, aldarate metabolism, and enriched in metabolic pathways, including bile secretion, ascorbate and aldarate metabolism. Cross-dataset analysis identified 29 common DEGs, from which a PPI network of 16 hub genes was constructed. Importantly, independent validation confirmed a strong concordance (r = 0.576) between the CLP-seq discovery cohort and the experimental CLP-seq data. Lcn2, S100a8, S100a9, Lrg1 and the TNF/IL-17 signaling pathways were robustly verified. CLP and LPS models demonstrate convergent hippocampal transcriptomic profiles distinct from PCI. Lcn2, S100a8, S100a9, Lrg1 and the TNF and IL-17 signaling pathways are highly reliable core features in SAE.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation, therapy resistance, and extensive invasion, largely driven by epithelial-mesenchymal transition (EMT). Longikaurin A (LK-A), a natural kaurane diterpenoid, has demonstrated promising anti-cancer properties, yet its role in EMT regulation within GBM remains unclear. This study aimed to systematically investigate the inhibitory effects of LK-A on TGF-β1-induced EMT and to elucidate the underlying molecular mechanisms contributing to its anti-invasive potential in GBM. LK-A inhibited EMT-associated phenotypic changes, including reduced expression of mesenchymal markers (N-cadherin, Vimentin) and increased expression of epithelial markers (ZO-1, Occludin), alongside suppression of key EMT transcription factors (Snail, Twist1). Functionally, LK-A impaired EMT-induced cell migration, invasion, and glioma stem cell-like traits, evidenced by decreased gliosphere formation and downregulation of stemness markers such as Sox2 and Oct4. Mechanistic analyses revealed that LK-A triggered reactive oxygen species (ROS) accumulation, leading to the activation of the JNK/p38 MAPK signaling cascade. Pharmacological inhibition of JNK or ROS scavenging reversed the anti-EMT effects of LK-A, confirming that EMT suppression is mediated through ROS-dependent JNK activation. In vivo, LK-A significantly suppressed tumor growth, EMT marker expression, and stemness in xenograft models. Collectively, these findings identify LK-A as a potent regulator of EMT and glioma stemness via ROS/JNK signaling. This work provides new mechanistic insight into the anti-tumor effects of LK-A and highlights its potential as a promising therapeutic strategy for combating GBM aggressiveness.

TANK binding kinase 1 (TBK1) is serine/threonine protein kinase member of the inhibitor of nuclear factor-kB kinase family, with links to the etiology of familial as well as idiopathic Amyotrophic Lateral Sclerosis. It contributes to several regulatory cellular processes such as autophagy, inflammation and apoptosis. Reduction or loss of TBK1 kinase activity is associated with increased risk of ALS, and so understanding the molecular basis of this activity is an important research priority. In this current study, the role of the E168 residue, located adjacent to the active site of TBK1, has been assessed using a combination of artificial and naturally occurring variants found at this codon - evaluated using multiple readouts for TBK1 kinase activity. The results suggest that the negative charge resulting from the presence of a glutamic acid at this codon is a constitutive activator of TBK1 activity.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by continuous cognitive deterioration, primarily resulting from the accumulation of amyloid-β (Aβ) plaques and tau-induced neurofibrillary tangles (NFTs). Recent studies have also highlighted histone deacetylase 3 (HDAC3) as a critical suppressor of synaptic plasticity. Although pharmacological inhibition of HDAC3 has been shown to facilitate long-term potentiation (LTP), the precise relationship between HDAC3 activity and AMPA receptor signaling, key components in LTP induction and maintenance, remains insufficiently understood. Electroacupuncture (EA), known to modulate epigenetic markers like H3K9/H3K27 acetylation and HDAC3/4 activity, may offer therapeutic potential by targeting these pathways. Here, we investigated EA's effects on AD-related pathology in APP/PS1 transgenic mice, focusing on HDAC3-AMPA receptor interactions in synaptic plasticity. Behavioral assays (Morris water maze) and electrophysiological recordings revealed that EA improved spatial learning ability and reinstated LTP in APP/PS1 transgenic mice. Mechanistically, EA reduced hippocampal HDAC3 expression while upregulating GluR1/GluR2 subunits and increasing acetylated H3K9K14/H3 levels, suggesting HDAC3-mediated transcriptional regulation of AMPA receptor genes. Co-immunoprecipitation assays further supported HDAC3's physical interaction with AMPA receptor components. Crucially, conditional knockout of HDAC3 in neurons rescued both LTP impairments and memory deficits, reinforcing its pivotal role in synaptic dysfunction. Our findings unveil a novel epigenetic mechanism whereby EA mitigates AD-associated synaptic damage by suppressing HDAC3 and enhancing AMPA receptor-dependent plasticity, highlighting HDAC3 as a promising therapeutic target for AD intervention.

Tramadol withdrawal presents a significant clinical challenge, characterized by neurobehavioral impairments linked to neuroinflammation, oxidative stress and neurotransmitter dysregulation. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducer 14 (Fn14) pathway and downstream effectors like cAMP response element binding protein (CREB) are implicated, but effective targeted therapies are lacking. Aurintricarboxylic acid (ATA), a TWEAK inhibitor, exhibits neuroprotective potential. This study aims to evaluate the therapeutic efficacy of ATA in mitigating the tramadol withdrawal-induced neurobehavioral alterations in mice model, focusing on the role of TWEAK/Fn14 pathway and CREB phosphorylation. Swiss albino mice were subjected to chronic tramadol administration (50 mg/kg, s.c.) for 57 days, with withdrawal precipitated with naloxone (5 mg/kg, i.p.) on day 57. Behavioural assessments included withdrawal severity score (WSS), jumping frequency, and hyperalgesia. Biochemical analyses measured the level of oxidative stress markers (TBARS, SOD, GSH and catalase), inflammatory biomarkers (TNF-α, IL-6, IL-1β), and neurotransmitters (glutamate, dopamine and serotonin). ATA (5 mg/kg and 10 mg/kg i.p.) dose-dependently reduced the WSS, jumping frequency and hyperalgesia. It also mitigated the oxidative stress, neuroinflammation, and glutamate level, while restoring the neurotransmitter level. Notably, pretreatment with CREB inhibitor (666 - 15) (10 mg/kg i.p) significantly attenuated the protective effect of ATA, underscoring the pivotal role of CREB phosphorylation in its mechanism. Our findings demonstrate that ATA offers significant neuroprotection against tramadol withdrawal, primarily by inhibiting the TWEAK/Fn14 pathway and subsequently promoting the CREB phosphorylation. This study highlights ATA as a promising therapeutic candidate for managing tramadol withdrawal syndrome by targeting oxidative stress, neuroinflammation, and its downstream effectors.

Tauopathies, including Alzheimer's disease (AD), are neurodegenerative diseases characterized by abnormal tau aggregation in neurons and glial cells. Various tauopathy mouse models have been developed, including PS19, a tau-overexpressing transgenic mouse model with the P301S mutation, in which glial activation has been reported prior to the accumulation of tau. In this mouse model, tau pathology was improved by the administration of the immunosuppressant FKB506, suggesting that inflammatory responses promote the progression of tau pathology. Our previous studies have shown that the inhibition of Collapsin response mediator protein 2 (CRMP2) phosphorylation suppresses inflammation and ameliorates pathological progression in spinal cord injury and MPTP-induced Parkinson's disease models using CRMP2KI/KI mice, in which the phosphorylation site Ser522 was replaced with Ala. Therefore, we compared glial cell activation in male PS19 and PS19; CRMP2KI/KI mice using morphometric analysis at 5 months of age, before the onset of tau pathology. We found that the morphological changes caused by the activation of microglia and astrocytes were normalized by suppressing CRMP2 phosphorylation compared with those in PS19 mice. Cox-2 expression in hippocampal neurons was increased in PS19 mice, but this increase was suppressed in PS19; CRMP2KI/KI mice, suggesting that the suppression of CRMP2 phosphorylation in neurons is also involved in this process. These results suggest that the inhibition of CRMP2 phosphorylation may improve neuroinflammation in tauopathy.

Mitochondrial diseases (MDs) are heterogeneous multisystemic disorders often caused by genetic defects in either nuclear or mitochondrial DNA. Although next-generation sequencing technologies have dramatically expanded the number of variants associated with these diseases, many remain variants of unknown significance (VUS). This review explores the utility of zebrafish (Danio rerio) as a vertebrate model system for studying mitochondrial dysfunction, with a focused analysis on the application of morpholino oligonucleotides (MOs) to functionally characterize and interpret VUS. MO-induced knockdown produces a transient suppression of target genes during zebrafish early development, recapitulating key MD phenotypes. Furthermore, rescue experiments involving co-injection of MO and either wild-type or mutant mRNA have proven useful to functionally assess the pathogenicity of specific variants. Specifically, while wild-type mRNA rescues the morphant phenotype, failure of mutant mRNA to do so confirms the variant's pathogenic effect. This approach has successfully linked previously uncharacterized genes to MD and helped reclassify ambiguous variants. The use of MO-based strategies in zebrafish remains a valuable tool for variant interpretation and functional validation, bridging the gap between genomic data and clinical action, and ultimately reducing the diagnostic odyssey. Overall, this review places MO knockdown and rescue assays in zebrafish as a robust and versatile platform to address functional genomics in MD research.

Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.

This study investigates the influence of sex on region-specific neural vulnerability following global cerebral ischemia using a Bilateral Common Carotid Artery Occlusion (BCCAo) mouse model that mimics severe ischemic brain stroke condition in humans. Comprehensive behavioral assessments, neuropathological analyses, and molecular profiling were conducted across multiple time points post-ischemia in male and female CD1 mice. Both sexes exhibited early motor deficits, cortical-striatal mitochondrial dysfunction, inflammation, and cell death at day 1, with gradual behavioral recovery. However, the hippocampus demonstrated a clear sex-specific divergence: males exhibited delayed yet prolonged inflammation, apoptotic cell death, and increased autophagy/mitophagy activity, while females were largely protected despite hypoxic and inflammatory gene expression. Molecular assays revealed prolonged upregulation of hypoxia-inducible factor 1α (HIF-1α), IL-1β, IL-6, TNF-α, and apoptotic markers in males, especially in the hippocampus, alongside increased expression of autophagy (Beclin-1, LC3-II, ATG7) and mitophagy (PINK1, BNIP3L) regulators and a shift in mitochondrial dynamics favoring fission.