NeuroMolecular Medicine最新文献

Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. However, effective therapies that modify the disease process in AD remain elusive. Far-infrared radiation (FIR) is commonly utilized as a complementary treatment a range of disease, for example insomnia and rheumatoid arthritis. In this research, we explored how FIR light impacts the cognitive functions of TgCRND8 AD mice and elucidated its underlying molecular mechanism. The cognitive capabilities of TgCRND8 mice assessed by employing the Morris water maze. The concentrations of IL-1β, TNF-α, IL-4, Aβ40, and Aβ42 protein were assessed by enzyme-linked immunosorbent assay. Immunostaining was conducted to assess the Aβ deposits and microglial presence in the brains of TgCRND8 mice. Western blot was applied to detect the protein expressions of tau phosphorylation, amyloid-β (Aβ) production, Jak-2/Stat3, and Nrf-2/HO-1 pathways. The results indicated that FIR light notably ameliorated the cognitive impairments of the AD mice, reduced both Aβ deposition and tau protein hyperphosphorylation at sites of Thr205, Ser369, Ser404, and Thr181, suppressed the release of TNF-α and IL-1β, attenuated the ratios of p-Jak-2/Jak-2 and p-Stat3/Stat3, while increased the protein levels of IL-4, Nrf-2, and HO-1 in the brains of TgCRND8 mice. These findings amply demonstrated that FIR light ameliorated cognitive deficits of TgCRND8 mice via reducing both Aβ burden and tau protein hyperphosphorylation, suppressing the neuroinflammation, and restoring the levels of the oxidative-related proteins through modulating Jak-2/Stat3 and Nrf-2/HO-1 pathways. These experimental findings indicate that FIR light treatment is a promising treatment approach for AD.

Embryonic cerebrospinal fluid (E-CSF) has an important role in neurological development. Due to limited availability, the composition and properties of E-CSF are not known to the present. Our review aims to offer a comprehensive perspective over the studies published to date regarding the composition and effects of E-CSF. We performed a systematic search of four databases for studies regarding normal E-CSF, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We screened 725 records for eligibility criteria, resulting in 44 studies included in the narrative synthesis. Of these, four compared E-CSF with postnatal CSF, and three studies used human E-CSF for composition description. The most comprehensive set of molecular analyses was performed via mass spectrometry, in four studies. We observed a decrease in the number of published studies in the last 5 years. All included studies showed better results when cells were cultured in E-CSF than basal medium. Research on E-CSF remains sparse, particularly concerning its role in human developmental neurobiology. The heterogeneous nature of the study designs and experimental approaches showcase the need for standardized methodologies to better understand the unique properties and potential clinical applications of E-CSF.

Insulin receptor substrate 1 (IRS-1) is a key mediator of insulin signaling linked to focal cortical dysplasia. While previous studies have primarily focused on IRS-1 in peripheral tissues, its function in the central nervous system has remained largely unexplored. This study aimed to investigate the spatiotemporal expression patterns of IRS-1 protein in mouse cerebral cortex and human brain organoids, along with its role in neural development. In mice, Irs-1 expression was consistent throughout brain development, with notable localization in the ventricular/subventricular zone during early gestation and later in the outer cerebral cortex. In human brain organoids, IRS-1 was primarily found in rosette structures initially, shifting to the outer cortical layer as they matured. Knockdown of Irs-1 at embryonic day 14.5 via in-utero electroporation impaired neuronal migration, resulting in more neurons remaining in the intermediate zone compared to controls. Moreover, SH-SY5Y cells treated with isotretinoin exhibited a significant decrease in IRS-1 protein expression during maturation. RNA sequencing indicates an upregulation of neurodevelopment-related genes alongside a downregulation of the IRS-1. These findings underscore the significance of IRS-1 in brain development, particularly regarding neuronal migration and differentiation.

The cognitive impairment resulting from stroke is purported to be associated with impaired neuronal structure and function. Transcranial Magnetic Stimulation (TMS) modulates neuronal or cortical excitability and inhibits cellular apoptosis, thereby enhancing spatial learning and memory in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. In this study, we aimed to investigate whether Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1), a pivotal Toll-like receptor adaptor molecule and its related mechanisms are involved in the ameliorating effect of TMS on cognitive function post-cerebral ischemia. We evaluated hippocampal injury in MCAO/R rats after one week of treatment with 10-Hz TMS at an early stage. The effect of SARM1 was more effectively assessed through lentivirus-mediated SARM1 overexpression. Various techniques, including FJB staining, HE staining, western blot, immunofluorescence, imunohistochemistry, and transmission electron microscopy, were employed to investigate the molecular biological and morphological alterations of axons, myelin sheaths and apoptosis in the hippocampus. Ultimately, Morris Water Maze was employed to evaluate the spatial learning and memory capabilities of the rats. We observed that TMS significantly reduced the levels of SARM1, NF-κB, and Bax following MCAO/R, while elevating the levels of HSP70, Bcl-2, GAP-43, NF-200, BDNF, and MBP. Overexpression of SARM1 not only reversed the neuroprotective effects induced by TMS but also exacerbated spatial learning and memory impairments in rats. Our results demonstrate that TMS mitigates hippocampal cell apoptosis via the SARM1/HSP70/NF-κB signaling pathway, thus fostering the regeneration of hippocampal axons and myelin sheaths, as well as the improvement of spatial learning and memory.

Deregulated reactive oxygen species (ROS) levels trigger oxidative stress (OS) injury that is closely associated with the pathophysiology of various neurological disorders. Therefore, therapeutic efforts at oxidative events in the pathway of neuronal degeneration would be promisingly helpful for intervention and treatment of related diseases. Here, we report that gastrodin, the main bioactive constituent of Rhizoma Gastrodiae, protects the mouse hippocampal HT22 cells from OS caused by hydrogen peroxide (H₂O₂), including the increased cell viability, elevated Glutathione (GSH) levels, decreased Malondialdehyde (MDA) activity, and down-regulated ROS levels with restored cell morphology. Through RNA-sequencing (RNA-Seq) and multiple experiments, we screened the gene Mamdc2 that could be a potential regulating target of gastrodin. Mechanistically, gastrodin exerts its protective effects on neuronal cells from oxidative injury by suppressing miRNA-125b-5p, which increases its target Mamdc2 expression. Overexpression of miR-125b-5p mimics significantly attenuates the gastrodin-triggered protective effects against H₂O₂ in HT22 cells, including the decreased cell viability, down-regulated GSH activity, increased MDA activity, and up-regulated ROS production, compared to the gastrodin-administration with control miRNA group. However, these results could be effectively restored by the ectopic expression of Mamdc2, leading to the opposite outcomes to those of miR-125b-5p mimics-overexpression. Thus, the current study provides evidence that gastrodin has the potential for intervention and therapy of OS injury-associated neurological diseases in future.

Traumatic brain injury (TBI) induces profound functional heterogeneity in astrocytes, yet the regulatory mechanisms underlying this diversity remain poorly understood. In this study, we analyzed single-cell RNA sequencing data from the cortex and hippocampus of TBI mouse models to characterize astrocyte subtypes and their functional dynamics. We identified two major reactive subtypes: A1 astrocytes, enriched in inflammatory response, synaptic regulation, and neurodegenerative disease-related pathways; and A2 astrocytes, enriched in lipid metabolism, extracellular matrix (ECM) remodeling, and phagosome formation pathways. These functional differences were consistently observed across datasets with varying injury severities. Notably, adhesion-related pathways-including gap junctions, adherens junctions, and calcium-dependent adhesion-showed significant subtype-specific expression patterns and temporal shifts. Pseudotime trajectory analysis further suggested a potential transition between A1 and A2 states, accompanied by dynamic regulation of adhesion-related genes. Our findings highlight the complex and context-dependent roles of astrocytes in TBI and propose cell adhesion as a key modulator of astrocyte functional polarization.

NeuroD2 (ND2), a neuron-specific transcription factor, is essential in neural differentiation and neuroplasticity, yet its regulation under neuronal injury is barely uncovered. Effective treatment strategies for ischemic conditions require extensive knowledge of the signaling pathways and mechanisms underlying ischemic pathophysiology. This study aims to uncover the neuroprotective role of ND2 in ischemia and its interactions with critical signaling pathways implicated in recovery. An in vitro ischemic stroke model oxygen-glucose deprivation (OGD) method was applied to neuro-2A (N2a) cells with lentiviral ND2 (LvND2) overexpression. DNA fragmentation and cell survival assays indicated ND2's neuroprotective and anti-apoptotic effects under OGD conditions. Proteomic profiling and interaction analyses showed that LvND2 regulated the synthesis of cellular signaling, proliferation and cell adhesion-related proteins, such as MAPK3, Mki67, and NCAM. Additionally, a positive correlation was observed between ND2 expression and phosphorylated AKT levels. To investigate the interaction between ND2 and the PI3K/AKT signaling pathway, the pathway was pharmacologically inhibited with Wortmannin 30 min before OGD induction. After 8 h of OGD followed by 16 h of reperfusion, cell survival, DNA fragmentation, and Western blot analyses were performed. LvND2 administration alone increased cellular survival, whereas its combination with Wortmannin resulted in decreased cell survival. Additionally, LvND2 alone reduced the number of TUNEL-positive cells, while its combination with Wortmannin remains non-significant. These findings suggest that ND2 and AKT function in a coordinated manner within the PI3K/AKT survival pathway. ND2 may modulate AKT activity, highlighting its potential as a therapeutic target for addressing ischemic pathophysiology through molecular therapies.

Glutamatergic neurons of the dorsal root ganglion (DRGg) exert a significant effect on peripheral nociceptive signal transmission. However, assessing the explicit modulatory effect of DRGg during chronic neuropathic pain (CNP) with neuromodulation techniques remains largely unexplored. Therefore, we inhibited DRGg by optogenetic stimulation and examined whether it could alleviate CNP and associated anxiety-related behaviors in a chronic compressed DRG (CCD) rat model. The CCD pain model was established by inserting an L-shaped rod into the lumbar 5 (L5) intervertebral foramen, and either AAV2-CaMKIIα-eNpHR3.0-mCherry or AAV2-CaMKIIα-mCherry was injected into the L5 DRG. Flexible optic fibers were implanted to direct yellow light into the L5 DRG. Pain and anxiety-related behavioral responses were assessed using mechanical threshold, mechanical latency, thermal latency, and open field tests. In vivo single-unit extracellular recording from the DRG and ventral posterolateral (VPL) thalamus was performed. CNP and anxiety-related behavioral responses along with increased neural firing activity of the DRG and VPL thalamus were observed in CCD animals. Enhanced expression of nociception-influencing molecules was found in the DRG and spinal dorsal horn (SDH). In contrast during optogenetic stimulation, specific DRGg inhibition markedly alleviated the CNP responses and reduced the DRG and VPL thalamic neural hyperactivity in CCD animals. Inhibition of DRGg also reduced the active expression of nociceptive signal mediators in the DRG and SDH. Taken together, our findings suggest that CaMKIIα-NpHR-mediated optogenetic inhibition of DRGg can produce antinociceptive effects in CCD rats during peripheral nerve injury-induced CNP condition by altering peripheral nociceptive signal input in the spinothalamic tract.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by complex pathophysiology and significant clinical challenges. Emerging research emphasizes the crucial role of neuropeptides in GBM and its influence on tumor progression, immune modulation, and therapy resistance. This review highlighted the importance of neuropeptides and their receptors in maintaining brain homeostasis and the glioblastoma tumor microenvironment. We discussed new therapeutic frontiers, including neuropeptide receptors as therapeutic targets, renin-angiotensin system, peptide receptor modulation, targeted cytotoxic analogs (such as Bombesin and Somatostatin), and advances in targeted radiotherapy. The review highlighted the potential of neuropeptide-based targeted therapies to improve GBM patient outcomes and suggests future research directions. This underscores the importance of targeting neuropeptide-related pathways for innovative therapeutic strategies in GBM, aiming to enhance patient prognosis and effective treatment.