Frontiers in Molecular Neuroscience最新文献

Arterial hypertension is considered a main risk factor for cognitive impairment and stroke. Although chronic hypertension leads to adaptive changes in the lager cerebral blood vessels which should protect the downstream microvessels, profound changes in the structure and function of cerebral microcirculation were reported in this disease. The structural changes lead to dysregulation of the neurovascular unit and manifest themselves in particular as endothelial dysfunction, disruption of the blood-brain barrier and impairment of neurovascular coupling. The impairment of neurovascular coupling results in inadequate functional hyperemia, which in turn may lead to cognitive decline and dementia. In this review the effects of chronic arterial hypertension on the essential components of neurovascular unit involved in neurovascular coupling such as endothelial cells, astrocytes and pericytes are discussed.

Introduction: Oxidative stress is a central driver of brain aging, impairing cellular function and increasing susceptibility to neurodegenerative diseases. Recent studies suggest that the RNA demethylase FTO regulates N6-methyladenosine (m6A) RNA modification, a key pathway in modulating oxidative stress in the brain. However, the precise mechanisms underlying FTO's role remain unclear. This study examines the neuroprotective potential of MO-I-500, a small-molecule FTO inhibitor, against oxidative stress induced by tert-butyl hydroperoxide (TBHP) in neuron-like SH-SY5Y cells differentiated with retinoic acid and BDNF (dSH-SY5Y).

Methods: dSH-SY5Y cells were treated with MO-I-500 alone for 72 h or with TBHP alone for 24 h. Alternatively, cells were pretreated with 1 μM MO-I-500 for 48 h, followed by co-treatment with MO-I-500 and 25 or 50 μM TBHP for an additional 24 h, for a total treatment duration of 72 h. Cellular metabolism was assessed using a Seahorse XF MitoStress assay, and oxidative stress markers, including ROS and superoxide levels, were quantified with DCFDA and MitoSOX probes. ATP content was measured using a bioluminescence assay.

Results: FTO inhibition by MO-I-500 induced a metabolic shift toward an energy-efficient state, enhancing cellular resilience to oxidative stress. Pretreatment significantly reduced TBHP-induced oxidative damage, lowering intracellular ROS levels and preserving ATP content.

Conclusion: Together with our previous findings demonstrating the protective effects of MO-I-500 in astrocytes and recent studies supporting the importance of astrocyte function in neurodegeneration, these results suggest a dual protective role of MO-I-500 in neurons and astrocytes. This dual action positions MO-I-500 as a promising therapeutic strategy to mitigate oxidative damage and reduce the risk of neurodegenerative diseases, including Alzheimer's disease.

Mutations in α-synuclein (α-syn) and LRRK2 cause familial Parkinson's disease (fPD), yet how these proteins functionally interact remain ambiguous. We previously showed that α-syn undergoes bi-directional transport within axons and influences mitochondrial health, while other studies suggested that LRRK2-G2019S disrupts the axonal transport of autophagic vesicles and mitochondria. Here we tested the hypothesis that α-syn and LRRK2 are functionally linked during axonal transport. Expression of human LRRK2-WT in Drosophila larval nerves caused modest CSP-containing axonal blockages whereas no defects were seen in LRRK2 loss of function mutants in contrast to other proteins directly involved in axonal transport. Surprisingly, fPD mutations in the GTPase (LRRK2-Y1699C) and WD40 (LRRK2-G2385R) domains suppressed axonal blocks compared to LRRK2-WT, while kinase-domain mutant G2019S enhanced them. Reducing kinesin-1 had no effect with LRRK2-WT, but increased axonal transport defects with LRRK2-G2385R suggesting a functional interaction between the LRRK2 WD40 domain and the anterograde transport machinery. Further, co-expression of α-syn with either the GTPase domain or WD40 domain LRRK2 fPD mutants significantly suppressed α-syn-mediated axonal transport defects, decreased stalled α-syn-vesicles, but did not alter α-syn-mediated neuronal cell death. Taken together, these results suggest that while LRRK2 itself may not play an independent role in axonal transport, its GTPase and WD40 domains likely associate functionally with α-syn during transport within axons.

Background: Spinal Cord Injury (SCI) is a severe central nervous system disorder that initiates inflammatory reactions, exacerbating tissue damage and impeding neuronal repair. Macrophage polarization plays a critical role in this pathological process: it significantly regulates inflammation resolution and tissue regeneration, rendering its modulation a key strategy for SCI repair. Omaveloxolone (Omav), a novel Nrf2 activator, has demonstrated potential in regulating inflammatory responses, suggesting it may serve as a promising candidate for SCI intervention.

Methods: To evaluate the efficacy and underlying mechanism of Omav in SCI repair, a spinal cord contusion model was established in animal subjects. Additionally, an in vitro lipopolysaccharide (LPS)-induced macrophage polarization model was constructed to further validate Omav's effects on macrophage phenotypes. RNA sequencing (RNA-seq) was employed to elucidate the molecular pathways through which Omav modulates post-SCI pathophysiology.

Results: In vivo experiments revealed that Omav effectively restored motor function in SCI-induced animals. RNA-seq analysis further demonstrated that Omav reshaped inflammatory cascades following SCI, with a significant impact on macrophage polarization dynamics. Specifically, Omav promoted the formation of an M2-dominant macrophage landscape (a phenotype associated with anti-inflammation and tissue repair) while reducing the pro-inflammatory M1 macrophage phenotype. These findings were corroborated by in vitro studies, which confirmed that Omav directly facilitated M2-type macrophage polarization.

Conclusion: Our results collectively confirm the efficacy of Omav in repairing spinal cord injury by targeting macrophage polarization and regulating inflammatory responses. This study not only highlights the therapeutic potential of Omav for SCI but also provides a novel pharmacological strategy for SCI treatment.

FK506-binding protein 51 (FKBP51) is a pivotal molecular chaperone and scaffolding protein that integrates and modulates multiple signaling pathways-including those involving HSP90, the glucocorticoid receptor, AKT, and NF-κB-through its FK1, FK2, and TPR domains, thereby playing a central role in the maintenance of central nervous system (CNS) homeostasis. This review systematically elaborates on the pathological mechanisms and therapeutic potential of FKBP51 in a variety of CNS disorders. In neurodegenerative diseases, FKBP51 promotes aberrant aggregation of Tau protein via the HSP90 complex, exacerbating the pathological progression of Alzheimer's disease; in Parkinson's disease, it influences neuronal survival through interaction with the PINK1/AKT signaling pathway; while in Huntington's disease, it impairs the clearance of mutant huntingtin (mHTT) protein. In models of ischemic stroke, upregulation of FKBP51 enhances autophagy and inflammatory responses through pathways such as AKT/FoxO3, thereby amplifying brain injury. In glioma, FKBP51 exhibits a context-dependent dual role: it may exert tumor-suppressive effects by inhibiting Akt, while its splice variant FKBP51s can regulate PD-L1 expression, promoting tumor immune evasion and therapy resistance. Emerging highly selective small-molecule inhibitors, gene-editing technologies, and novel applications of conventional drugs targeting FKBP51 have demonstrated significant interventional potential in preclinical studies. In summary, FKBP51 constitutes a pleiotropic signaling node, positioning it as a prime therapeutic target for a broad spectrum of CNS disorders.

Within the significant worldwide causes of mortality and morbidity are congenital heart diseases. Congenital cardiomyopathies include conditions in which early diagnosis and care can improve survival and health. In general, the first diagnostic tool is clinician suspicion followed by appropriate imaging, classically an echocardiogram. Cardiomyopathies have high rates of clinically detectable genetic causes. In view of this, prompt genetic testing is highly recommended for patients with cardiomyopathy. Genetic diagnosis, that is relevant to both the patient and family members, can help guide the selection of appropriate therapies and provide valuable information about the presence of comorbidities in other organ systems. Congenital Disorders of Glycosylation (CDG) are a growing group of inherited multisystem disorders characterized by defects in the glycosylation of proteins and lipids. Hypertrophic / dilated cardiomyopathy and neuromuscular abnormalities are recurrent manifestations of glycosylation defects. Mutations within the gene encoding the human transmembrane protein 165 (HsTMEM165), that belong to uncharacterized protein family 0016 (UPF0016), have been associated with cases of CDG. Recent progress in basic and clinical research related to TMEM165, focusing on the pathogenicity of HsTMEM165 variants, are reviewed. Highlights include the critical role of amino acid replacement for maintaining the structural and functional integrity of TMEM165 and their known associations with phenotypes of CDG patients. Future directions in this rapidly evolving area of research are proposed, to recognize the potential involvement of HsTMEM165 in congenital cardiomyopathies.

Introduction: Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice.

Methods and results: H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for 1 month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor.

Discussion: These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflamma.

Adolescence is a critical late phase of the neurodevelopment, characterized by marked brain plasticity and increased vulnerability to environmental challenges such as alcohol exposure. This study examined the impact of binge-like alcohol exposure in male Swiss Webster mice, focusing on oxidative damage, epigenetic and transcriptional alterations in key brain regions, such as the prefrontal cortex, cerebellum, striatum and hippocampus. Our results demonstrated that acute alcohol exposure during adolescence induces oxidative damage with significant alterations in global DNA methylation and gene expression involved in epigenetic regulation with distinct temporal and anatomical profiles. In the prefrontal cortex binge-like alcohol exposure exhibited persistent upregulation of genes associated with DNA methylation and histone deacetylation, consistent with prolonged transcriptional silencing that may impair executive functions and decision-making. The hippocampus appeared particularly sensitive, exhibiting marked decreases in DNA methylation and gene expression changes associated with an open chromatin state leading potentially linked to cognitive impairments in memory and learning impairments in memory and learning. In the striatum, binge-like alcohol exposure induced active DNA demethylation and transient modulation of histone methyltransferases, reflecting a dynamic compensatory response to alcohol-induced transcriptional repression, with implications for reward processing and impulse control. Similarly the cerebellum displayed a biphasic transcriptional pattern suggesting adaptive or homeostatic mechanisms aimed at maintaining cellular and synaptic balance. Collectively, these findings, accompanied by alterations in behavioral tests, highlight the regional specificity of epigenetic remodeling induced by excessive alcohol exposure during adolescence and offer new insights into the molecular mechanisms underlying increased neurodevelopmental vulnerability during this period.