Acta Neuropathologica Communications最新文献

In response to the groundbreaking study by Stepankova et al. (Acta Neuropathol Commun 13:89, 2025) demonstrating that activated α9 integrin enables sensory axon regeneration after spinal cord injury, this letter provides a critical perspective on the mechanistic underpinnings and translational implications of their findings. While acknowledging the significance of identifying α9 integrin as a potent pro-regenerative driver, we highlight several areas requiring deeper investigation. Specifically, we interrogate the precise ligand-receptor interactions within the inhibitory injury environment and potential crosstalk with inhibitory signaling pathways. Furthermore, we raise critical concerns regarding the long-term stability and functional specificity of the regenerated sensory circuits, emphasizing the risk of maladaptive synaptogenesis leading to neuropathic pain. Finally, we contextualize these findings within the challenges of clinical translation, arguing that the efficacy of this approach must be validated in more severe, contusive injury models that better recapitulate the human pathology. This critical analysis aims to frame the essential next steps required to transform this compelling biological discovery into a viable therapeutic strategy.

Epigenetic modifications play crucial roles in glioblastoma growth and aggressiveness, with key regulators including histone deacetylases (HDACs), histone acetyltransferases (HATs), and methyltransferases. Targeting these epigenetic alterations has emerged as a promising therapeutic strategy, utilizing DNA methyltransferase (DNMT) inhibitors, HDAC inhibitors (HDACis), and miRNA-based therapies. HDACis, whose effect on p53, p21, Bax, and Bcl-2, have gained significant interest because of their ability to restore the expression of tumor suppressor genes, thereby inducing apoptosis and overcoming therapeutic resistance. Our study demonstrated that a novel hydroxamic acid analogue, compound 3B, effectively inhibited glioma cell (C6) proliferation and exhibited potent anticancer activity. Compound 3B induced G2/M phase cell cycle arrest, increased apoptotic cell populations, and significantly reduced colony formating efficiency. Confocal imaging revealed nuclear condensation and elevated reactive oxygen species (ROS) levels, indicating oxidative stress. Western blot analysis confirmed that HDAC inhibition increased AcH3K9 protein levels. Further, studies in in vivo xenograft model and allograft C6 Wistar rat model revealed strong antitumour activity, suggesting that compound 3B is a promising therapeutic candidate for glioblastoma treatment.

Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL/6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFRβ-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFRβ and CD13 in isolated cerebral microvessels and flow cytometric analysis of brain cells. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFRβ expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFRβ concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFRβ expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFRβ expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFRβ by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.

Subarachnoid hemorrhage (SAH) is a devastating neurological condition with limited therapeutic options for mitigating secondary brain injury. This study investigates the neuroprotective potential of exosomes derived from human neural stem cells (hNSC-exo) in a rat SAH model, focusing on their molecular mechanisms through single-cell RNA sequencing (scRNA-seq) and transcriptomic profiling. This study demonstrated that hNSC-exo administration significantly ameliorated neurological deficits, reduced blood-brain barrier (BBB) disruption, and attenuated neuronal damage post-SAH. Behavioral assessments revealed improved cognitive and motor recovery in hNSC-exo-treated rats, supported by histopathological evidence of preserved neuronal architecture and reduced edema. scRNA-seq analysis revealed a marked increase in astrocyte proportions and vitality following hNSC-exo treatment, alongside suppression of neurotoxic microglial activation. Transcriptomic profiling identified the BDNF/TRKB signaling pathway as a critical mediator, with hNSC-exo upregulating BDNF and TRKB expression both in vivo and in vitro. Functional validation confirmed that hNSC-exo enhanced astrocyte survival via BDNF/TRKB activation, while knockdown of BDNF or TRKB reversed these protective effects. Furthermore, hNSC-exo mitigated neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-18) and microglial C1q expression. These findings highlight hNSC-exo as a novel therapeutic strategy for SAH, leveraging astrocyte-mediated neuroprotection and BDNF/TRKB pathway activation to counteract secondary injury. This study provides mechanistic insights into exosome-based therapies and underscores their potential for clinical translation in cerebrovascular disorders.

Chronically inflamed, reactive microglia represent a prominent feature of secondary progressive multiple sclerosis (SPMS). Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the treatment of active SPMS, to inhibit disease-associated T cell-microglia interactions using a chronic murine experimental autoimmune encephalomyelitis (EAE) model of MS. We found that therapeutic siponimod treatment of chronic EAE improved clinical severity accompanied by reduced demyelination and neuroaxonal damage, diminished CNS T cell infiltration and altered proinflammatory microglia responses. This effect was partly attributed to a direct effect on microglia, as siponimod pretreatment inhibited interferon-γ-elicited responses of primary mouse microglia in vitro and limited their ability to induce T cell activation and proliferation in T cell-microglia co-cultures. Additionally, we observed reduced peripheral T cell numbers in our EAE model, with a pronounced shift to immunosenescent and regulatory T cell subsets, a pattern which we similarly detected in a cohort of SPMS patients following siponimod treatment. These findings indicate that siponimod dampens compartmentalized CNS inflammation by disrupting detrimental interactions between T cells and microglia through a dual central and peripheral mechanism of action.

Painful neuromas remain a major clinical challenge after limb amputation and peripheral nerve trauma. While histological features such as inflammation, fibrosis, and axonal sprouting have been proposed as contributors to neuropathic pain, direct clinicopathological correlations remain inconsistent. The role of internal nerve architecture, particularly the proportion of preserved, organized fascicular tissue, has not been quantitatively assessed in relation to pain intensity. To address this gap, this study investigates whether the relative amount of organized versus unorganized nervous tissue within neuromas correlates with patient-reported pain, independent of classical histological parameters. Accordingly, we performed whole-slide histological segmentation of peripheral nerve samples including control nerves, non-painful neuromas, and painful neuromas. Tissue compartments, including organized fascicles, unorganized neuroma tissue, connective tissue, and adipose tissue, were quantified and correlated with clinical pain scores. Our results demonstrate that painful neuromas exhibited a significantly lower relative amount of organized nervous tissue compared to non-painful neuromas (p = 0.006), while total nerve size and other tissue components showed no significant differences. A strong negative correlation was observed between pain intensity and the relative amount of organized fascicular tissue (r = - 0.82, p < 0.001). No correlation was found between pain and the absolute amount of unorganized nervous tissue or connective tissue. Taken together, these findings suggest that the structural preservation of organized nerve fascicles modulates the clinical expression of neuroma-related pain. Morphometric assessment of fascicular organization may provide a new biomarker for surgical planning and outcome prediction in neuroma management.

While neuroimaging studies have revealed notable white matter damage following mild traumatic brain injury (mTBI), the specific tracts and brain regions affected vary widely across studies. Here, we explored whether the spatial orientation of white matter tracts influences susceptibility to repeated mTBI, predicting that tracts oriented orthogonal to the axis of rotation of the head during impact (within the plane of rotation) would exhibit the most damage. Using a model of repeated rotational mTBI in mice, we acquired advanced diffusion MRI (diffusional kurtosis imaging using oscillating gradient encoding) and resting-state functional MRI (fMRI) data at baseline and 1-week post-injury. Consistent with our prediction, while both diffusivity and diffusional kurtosis decreased in the white matter of injured mice, only diffusional kurtosis revealed microstructural changes confined to tracts oriented orthogonal to the right-left axis of rotation. In addition, both region and subregion analyses showed functional connectivity (FC) deficits between regions connected via tracts running orthogonal to the rotation axis. The orientation-dependent changes in imaging metrics were validated by histopathological analyses. Females showed greater microstructural changes than males using diffusion MRI following injury, while no sex differences were detected by fMRI. Interestingly, the region-specific and subregion-specific FC analyses showed overlapping but non-identical changes in FC suggesting the utility of using both coarse and fine levels of brain parcellation for FC analyses in mTBI. These findings suggest that mTBI imaging studies may benefit from the consideration that damage after mTBI will predominate in tracts that are oriented orthogonal to the axis of rotation produced by the impact and that diffusivity and diffusional kurtosis as well as region and subregion-specific fMRI analyses can detect these changes.

Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.

Central nervous system (CNS) macrophages play key roles in viral neuropathogenesis and immune surveillance, yet their trafficking and trafficking dynamics between the CNS and peripheral lymphoid tissues remain poorly understood. To address this gap, we used intracisternal (i.c.) injection of fluorescent-superparamagnetic iron oxide nanoparticles (SPION) in SIV-infected macaques that we found labeled CNS CD68⁺CD163⁺CD206⁺ perivascular, meningeal, and choroid plexus (CP) macrophages. SPION⁺CD163⁺ macrophages were also detected in the optic nerves and cribriform area-potential routes of macrophage egress from the CNS. CD163⁺SPION⁺ macrophages labeled in the CNS were identified in the deep cervical lymph node (dCLN) and dorsal root ganglia (DRG). SPION⁺ CD163⁺ macrophages appeared in both the CNS and the periphery as early as 24 h post i.c. inoculation, decreasing over time in the CNS of non-infected animals but accumulating with SIV infection. A trend toward greater numbers of SPION ⁺ macrophages that traffic out of the CNS was observed in non-infected animals, a pattern not seen with SIV infection. Productively infected SPION⁺ cells were found in the CNS and dCLN of infected animals 7-28 days post i.c. injection. These findings support a model in which SPION ⁺ macrophages, some of which harbor virus, traffic between the CNS and peripheral lymphoid tissues. This is discussed with regard to HIV infection of the CNS and reseeding of the periphery with CNS virus.