Decoding sTREM2: its impact on Alzheimer's disease - a comprehensive review of mechanisms and implications.

Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). This review comprehensively examines sTREM2's involvement in AD, focusing on its regulatory functions in microglial responses, neuroinflammation, and interactions with key pathological processes. We discuss the dynamic changes in sTREM2 levels in cerebrospinal fluid and plasma throughout AD progression, highlighting its potential as a therapeutic target. Furthermore, we explore the impact of genetic variants on sTREM2 expression and its interplay with other AD risk genes. The evidence presented in this review suggests that modulating sTREM2 activity could influence AD trajectory, making it a promising avenue for future research and drug development. By providing a holistic understanding of sTREM2's multifaceted role in AD, this review aims to guide future studies and inspire novel therapeutic strategies.

Three-needle electroacupuncture ameliorates depressive-like behaviors in a mouse model of post-stroke depression by promoting excitatory synapse formation via the NGL-3/L1cam pathway.

Three-needle electroacupuncture (TNEA) has shown promise as a non-pharmacological treatment for post-stroke depression (PSD). However, the underlying mechanisms of its therapeutic effects remain unclear. In this study, we investigated the potential molecular and synaptic mechanisms by which TNEA ameliorates depressive-like behaviors in a mouse model of PSD. Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) to induce PSD and subsequently treated with TNEA for three weeks at specific acupoints (GV24 and bilateral GB13). Through a combination of behavioral tests, neuronal activation assessment, synaptic function examination, transcriptomic analysis, and various molecular techniques, we found that TNEA treatment significantly improved anxiety and depressive-like behaviors in PSD mice. These improvements were accompanied by enhanced neuronal activation in the medial prefrontal cortex (mPFC) and primary somatosensory cortex (PSC), as well as the promotion of excitatory synapse formation and transmission function in the mPFC. Transcriptomic analysis revealed that TNEA upregulated the expression of Netrin-G Ligand-3 (NGL-3), a postsynaptic cell adhesion molecule, in the mPFC. Further investigation showed that the extracellular domain of NGL-3 binds to the presynaptic protein L1cam, promoting the formation of Vesicular Glutamate Transporter 1 (vGluT1) puncta on neuronal dendrites. Notably, cortical neuron-specific knockout of NGL-3 abolished the antidepressant-like effects of TNEA in PSD mice, confirming the crucial role of the NGL-3/L1cam pathway in mediating the therapeutic effects of TNEA. These findings provide novel insights into the molecular and synaptic mechanisms underlying the therapeutic effects of acupuncture in the treatment of PSD and highlight the potential of targeting the NGL-3/L1cam pathway for the development of alternative interventions for PSD and other depressive disorders.

Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases.

Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining brain homeostasis. However, in neurodegenerative conditions, microglial cells undergo metabolic reprogramming in response to pathological stimuli, including Aß plaques, Tau tangles, and α-synuclein aggregates. This metabolic shift is characterized by a transition from oxidative phosphorylation (OXPHOS) to glycolysis, increased glucose uptake, enhanced production of lactate, lipids, and succinate, and upregulation of glycolytic enzymes. These metabolic adaptations result in altered microglial functions, such as amplified inflammatory responses and diminished phagocytic capacity, which exacerbate neurodegeneration. This review highlights recent advances in understanding the molecular mechanisms underlying microglial metabolic reprogramming in neurodegenerative diseases and discusses potential therapeutic strategies targeting microglial metabolism to mitigate neuroinflammation and promote brain health. Microglial Metabolic Reprogramming in Neurodegenerative Diseases This graphical abstract illustrates the metabolic shift in microglial cells in response to pathological stimuli and highlights potential therapeutic strategies targeting microglial metabolism for improved brain health.

Blockade of NF-κB and MAPK pathways by ulinastatin attenuates wear particle-stimulated osteoclast differentiation in vitro and in vivo.

Ulinastatin, a urinary trypsin inhibitor (UTI), is widely used to clinically treat lipopolysaccharide (LPS)-related inflammatory disorders recently. Adherent pathogen-associated molecular patterns (PAMPs), of which LPS is the best-studied and classical endotoxin produced by Gram-negative bacteria, act to increase the biological activity of osteopedic wear particles such as polymethyl-methacrylate (PMMA) and titanium particles in cell culture and animal models of implant loosening. The present study was designed to explore the inhibitory effect of UTI on osteoclastogenesis and inflammatory osteolysis in LPS/PMMA-mediated Raw264.7 cells and murine osteolysis models, and investigate the potential mechanism. The in vitro study was divided into the control group, LPS-induced group, PMMA-stimulated group and UTI-pretreated group. UTI (500 or 5000 units/ml) pretreatment was followed by PMMA (0.5 mg/ml) with adherent LPS. The levels of inflammatory mediators including tumour necrosis factor-α (TNF-α), matrixmetallo-proteinases-9 (MMP-9) and interleukin-6 (IL-6), receptor activation of nuclear factor NF-κB (RANK), and cathepsin K were examined and the amounts of phosphorylated I-κB, MEK, JNK and p38 were measured. In vivo study, murine osteolysis models were divided into the control group, PMMA-induced group and UTI-treated group. UTI (500 or 5000 units/kg per day) was injected intraperitoneally followed by PMMA suspension with adherent LPS (2×108 particles/25 µl) in the UTI-treated group. The thickness of interfacial membrane and the number of infiltrated inflammatory cells around the implants were assessed, and bone mineral density (BMD), trabecular number (Tb.N.), trabecular thickness (Tb.Th.), trabecular separation (Tb.Sp.), relative bone volume over total volume (BV/TV) of distal femur around the implants were calculated. Our results showed that UTI pretreatment suppressed the secretion of proinflammatory cytokines including MMP-9, IL-6, TNF-α, RANK and cathepsin K through down-regulating the activity of nuclear factor kappa B (NF-κB) and MAPKs partly in LPS/PMMA-mediated Raw264.7 cells. Finally, UTI treatment decreased the inflammatory osteolysis reaction in PMMA-induced murine osteolysis models. In conclusion, these results confirm the anti-inflammatory potential of UTI in the prevention of particle disease.

[Treatment of lumbar intervertebral disc herniation accompanying with lumbar instability with internal fixation and spinal fusion].

OBJECTIVE: To explore operative effect of lumbar intervertebral disc herniation accompanying with lumbar instability. METHODS: Form June 2000 to June 2006, 46 patients of lumbar intervertebral disc herniation accompanying with lumbar instability were treated with decompression through posterior approach, diskectomy, spinal fusion and vertebral pedicle internal fixation. Including 33 males and 13 females,the age was from 37 to 68 years with an average of 48 years. The course of disease was from 4 months to 20 years with an average of 3.5 years. There were simple segment in 21 cases, double segments in 22 cases, three segments in 3 cases. RESULTS: All patients were followed up for 12-45 months with an average of 25 months. All cases got solid fusion and clinical symptom improved obviously. According to clinical standard to evaluation, 32 cases obtained excellent result, 8 good, 6 fair. The rate of excellent and good was 86.9%. CONCLUSION: Diskectomy, spinal fusion and internal fixation can obtain satisfactory clinical effect for lumbar intervertebral disc herniation accompanying with lumbar instability.

[Alterations in myocardial function in early stage of sepsis in rabbits].

OBJECTIVE: To study the alterations in myocardial function in early stage of sepsis. METHODS: Twenty rabbits were randomly divided into two groups. In the control group (n=10) only laparotomy was done, and in the sepsis group the animals received cecal ligation and puncture (CLP). In both groups left ventricular catheter was placed via right internal carotid artery. Left ventricular systolic peak pressure (LVSP), maximal positive change in filling pressure versus time (+dp/dt max), maximal negative change in filling pressure versus time (-dp/dt max) were monitored, and serum troponin I (TnI) was measured per hour for five times (0, 1, 2, 3, 4 hours after operation). RESULTS: Compared to the basic levels, LVSP, +dp/dt max and -dp/dt max decreased significantly an hour after CLP in sepsis group (all P<0.05), with the tendency of decrease with elapse of time. Serum TnI increased significantly an hour after CLP in sepsis group, and continued to increase with the passage of time. In contrast, no significant change was observed in control group. CONCLUSION: Cardiac muscle is injured, and myocardial systolic and diastolic functions are depressed in early stage of sepsis in rabbit model.