Molecular and Cellular Neuroscience最新文献

Peripheral nervous system myelination requires tightly coordinated structural and calcium-dependent communication between sensory axons and Schwann cells, processes that are profoundly influenced by extracellular matrix architecture. Here we describe a neonatal mouse dorsal root ganglia explant co-culture grown on laminin-1 pre-polymerized in acidic acetate buffer at pH 4 (polylaminin). This optimized substrate induced spontaneous formation of MBP-positive myelin sheaths, accompanied by enhanced alignment of Schwann cells with neurite bundles. Polylaminin also promoted robust clustering of the neuregulin receptor ErbB2 and a substantial increase in Connexin-43 gap-junction clusters along Schwann cell processes compared with laminin assembled in neutral phosphate buffer at pH 7 or with Poly-l-lysine. Fura-2 calcium imaging demonstrated that cultures on polylaminin exhibited faster, larger, and more sustained Ca²⁺ transients after KCl depolarization and ATP stimulation, indicating superior neuron-glia coupling and excitability. In contrast, laminin at pH 7 preferentially supported neurite outgrowth and Schwann cell migration, whereas Poly-l-lysine showed limited organization and responsiveness. The study establishes a simple and reproducible in vitro platform in which laminin supramolecular organization directs DRG cells toward neuritogenic or myelinating phenotypes through integrin/FAK/AKT signaling. By reducing the complexity of myelin induction while preserving functional communication, this model offers a valuable tool to investigate early events of peripheral demyelination, Cx43-dependent dysfunction, and degenerative responses characteristic of neuropathies that often precede CNS involvement.

Ferroptosis, a regulated form of cell death mediated by iron-dependent lipid peroxidation, is implicated in the secondary phase of acute spinal cord injury (ASCI). However, its specific molecular network and interaction with inflammatory processes within the ASCI context remain elusive. We investigated the ferroptosis inhibitor Liproxstatin-1 in a rat T10 contusion model. Post-injury Liproxstatin-1 treatment was evaluated using behavioral assessments, histology, transcriptomics, and biochemical assays. ASCI triggered widespread transcriptomic changes, including altered expression of ferroptosis-related modules involved in lipid peroxidation, iron metabolism, and antioxidant defense. Liproxstatin-1 improved motor function and balance, reduced tissue cavitation, neuronal loss, and gliosis. Transcriptomic analysis indicated that Liproxstatin-1 modulated genes associated with inflammation, immune cell migration, and Toll-like receptor/NLRP3 signaling. In HT22 cells, Liproxstatin-1 counteracted Erastin-induced ferroptosis, reducing ROS, restoring glutathione, lowering lipid peroxidation, and downregulating HMGB1, TLR4, TNF-α, and NLRP3. In vivo, Liproxstatin-1 reduced iron deposition, restored glutathione, attenuated lipid peroxidation, reversed GPX4 downregulation, and suppressed inflammatory protein elevation. These findings indicate that Liproxstatin-1 confers neuroprotection in ASCI by concurrently inhibiting ferroptosis and associated inflammatory activation, thereby highlighting ferroptosis as a potential therapeutic target.

Exercise may be a potential disease-modifying therapy to improve physiological function in people living with dementia (PWD), though further evidence is required. The purpose of this randomized controlled trial (RCT) was to investigate whether a modified Otago Exercise Program (OEP) would improve markers of metabolic aging, cellular aging, and epigenetics relative to usual care alone in PWD. In this 6-month, parallel-group, assessor-blinded RCT (NCT05488951), 42 PWD (mean age 82.1 ± 8.1 years; mean MoCA score 10.0 ± 5.9; 35.7% female) were randomly allocated 1:1 to exercise (n = 21) or usual care (n = 21). The exercise group performed 30 min of physical therapist-supervised strength and balance exercises followed by 30 min of walking, 3×/week for six months, alongside usual care. The usual care group continued routine healthcare and social activities. Primary outcomes were changes in fasted blood biomarkers: kynurenine (metabolic aging), leukocyte telomere length (cellular aging), and global DNA methylation (epigenetics), assessed at baseline and 6 months. The intention-to-treat analysis included all 42 participants, and the per-protocol analysis included only those in the exercise group who completed ≥2×/week exercise (n = 9/21) and all usual care participants (n = 21). Intention-to-treat and per-protocol analyses revealed no statistically significant between-group differences in any biomarker. However, telomere length increased in the usual care group (7.90 ± 0.90 to 8.70 ± 0.90 kb), while there was no change in the exercise group (8.00 ± 0.90 to 7.90 ± 0.90 kb) from baseline to 6 months. While statistically significant group differences were not observed, our study demonstrates the feasibility of biomarker collection in PWD and reveals trends-particularly in telomere length-that warrant investigation in larger, adequately powered trials.

Ischemic stroke is a leading cause of death and disability with limited therapeutic options. Neuroinflammation, particularly microglial activation and phenotypic modulation, plays a crucial role in ischemic cerebral injury. AdipoRon (APR), an adiponectin receptor agonist, shows neuroprotective effects, but its role in modulating microglial phenotypic states after ischemic stroke remains unclear. Using a transient middle cerebral artery occlusion (tMCAO) model, we demonstrated that APR treatment significantly ameliorated neurological deficits caused by ischemic injury. Our findings revealed that APR markedly reduced CD16 expression while enhancing CD206 expression in microglia, suggesting its neuroprotective actions are closely associated with microglial phenotypic modulation. We further explored APR effects on autophagy, given its crucial role in regulating microglial phenotypic states. APR significantly enhanced autophagy, and this enhancement was partially reversed by 3-methyladenine (3-MA), concomitantly reversing APR-induced CD206-associated microglial phenotype and its anti-inflammatory effects. To delineate the underlying mechanism, we examined adiponectin receptor signaling and downstream AMPK pathway involvement. Using siRNA-mediated knockdown of AdipoR1 and AMPK inhibitor Compound C, we observed marked reduction in autophagy levels and impairment of APR regulatory effects on microglial phenotypic modulation and inflammation. Collectively, our findings indicate that AdipoRon alleviates ischemic cerebral injury by activating the AdipoR1-AMPK signaling pathway, which subsequently enhances autophagy to promote a microglial phenotypic shift characterized by decreased CD16 and increased CD206 expression. These findings provide novel insights into APR neuroprotective mechanisms and highlight its potential as a therapeutic agent for ischemic stroke.