Neural Regeneration Research最新文献

Over the past few decades, the Sonic Hedgehog protein has become a pivotal player in many biological processes, including tumourigenesis, embryonic development, and protective mechanisms after cerebral damage. The Sonic Hedgehog signaling pathway is crucial in the central nervous system, with implications in a diverse range of diseases, including Parkinson's disease, Alzheimer's disease, spinal cord injury, traumatic brain injury, depression, Sonic Hedgehog medulloblastoma, and stroke. In this comprehensive review, we examined Sonic Hedgehog from the perspective of canonical and non-canonical pathways, elucidating their complex connections to the central nervous system. Subsequently, we summarize the latest advancements in drug therapies that offer novel strategies for treating neurological diseases by modulating the Sonic Hedgehog protein. Finally, we summarize and extend the technologies and tools for studying the Sonic Hedgehog signaling field, with the aim of providing new research ideas and methods.

JOURNAL/nrgr/04.03/01300535-202606000-00053/figure1/v/2026-02-11T151048Z/r/image-tiff White matter injury is a key factor impacting stroke recovery. Physical exercise can promote white matter repair. Immune cells, especially regulatory T (Treg) cells, contribute to strengthening white matter integrity, yet little is known about the underlying mechanism. To examine this, we established a transient middle cerebral artery occlusion male mouse model. We found that physical exercise elevated brain Treg cells, thereby enhancing neurological recovery, reducing neuroinflammation, promoting myelin debris clearance, and accelerating white matter repair. Depletion of Treg cells caused a decrease in these positive effects of physical exercise. Mechanistically, the rise in osteopontin triggered by physical exercise is dampened when Treg cells are depleted. In addition, Treg-conditioned medium reduced oxygen-glucose deprivation/re-oxygenation-induced microglial inflammation and enhanced phagocytosis, which could be blocked by osteopontin antibodies. Importantly, although Treg infusion could mimic the protective effects of physical exercise, osteopontin blockade partially countered the effects of physical exercise and Treg cells. Finally, our sequencing data revealed a marked upregulation of C-X-C motif chemokine ligand 12 (CXCL12) mRNA expression subsequent to physical exercise, which was confirmed at the protein level. Stimulation of Treg cells with stroke brain lysates increased C-X-C motif chemokine receptor 4 (CXCR4) expression, indicating a potential role for the CXCL12-CXCR4 axis in recruiting Treg cells. These findings suggest that physical exercise promotes white matter repair after ischemic stroke by Treg cells.

The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury. This review provides a comprehensive overview of ErbB receptors and their ligands, highlighting canonical and non-canonical signaling mechanisms relevant to brain damage. We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation, gliosis, and neural repair. Special attention is given to its interplay with other critical pathways, including Notch signaling, and its roles within adult neurogenic niches, where it modulates neural stem cell behavior in response to damage. Based on accumulating preclinical evidence, we propose two therapeutic strategies for targeting ErbB signaling in brain injury: (1) dampening neuroinflammation through ErbB inhibition and (2) promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation. The first strategy is supported by studies, which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models. The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release. Diterpenes, by influencing the ErbB pathway, may uniquely bridge the gap between neuroprotection and regeneration. Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies. By dissecting these mechanisms, we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.

JOURNAL/nrgr/04.03/01300535-202606000-00057/figure1/v/2026-02-11T151048Z/r/image-tiff In Alzheimer's disease, microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of Alzheimer's disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis, and microglial responses. We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer's disease pathology. The objective of this study is to investigate the effects of Alzheimer's disease serum on microglial phagocytosis. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer's disease ( n = 30) and age-matched controls ( n = 30) (PRODEM study) on microglial phagocytosis. Exposure to Alzheimer's disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB ( TFEB ) and of ATPase H + transporting lysosomal V1 subunit B2 ( ATP6V1B2 ), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to the serum of future Alzheimer's disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls, depending on the presence of the apolipoprotein E ε4 allele in the Alzheimer's disease patients. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid. We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with Alzheimer's disease blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2 , possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels, suggesting an important role for dietary eicosapentaenoic acid in microglial function.

JOURNAL/nrgr/04.03/01300535-202606000-00054/figure1/v/2026-02-11T151048Z/r/image-tiff Neurite outgrowth and synaptogenesis are critical steps for functional recovery following ischemic stroke. Damaged axons of the central nervous system in adult mammals exhibit limited regenerative capacity, resulting in enduring neurological deficits. Recent findings from our research indicate that inhibition of Rho-associated kinase (ROCK)2 facilitates neuroprotection in different models of central nervous system diseases. In addition, our prior studies have demonstrated that axonal protection enhances the regeneration of injured axons. However, it remains unclear whether the axonal protection mediated by ROCK2 inhibition also facilitates synaptogenesis. In this study, we aimed to investigate the effects of inhibiting ROCK2 expression on synaptogenesis and neurogenesis in ischemic stroke using an shRNA-expressing adeno-associated virus (AAV) vector (AAV-sh.ROCK2). We demonstrated that AAV-sh.ROCK2 increased neurite outgrowth and facilitated synaptogenesis in vivo . Furthermore, AAV-sh.ROCK2 increased neuronal survival and promoted neurogenesis following middle cerebral artery occlusion surgery as well as long-term motor functional recovery after ischemia/reperfusion injury. Notably, AAV-sh.ROCK2 also stimulated serotonergic and dopaminergic axon sprouting after ischemia/reperfusion injury. Mechanistically, AAV-sh.ROCK2 activity resulted in increased anti-collapsin response mediator protein 2 activation and reductions in RhoA and ROCK2 expression. Our study identified ROCK2 as a critical regulator of synaptogenesis and neurogenesis, highlighting it as a promising target to facilitate neuroprotection and regeneration in ischemic stroke.

Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and non-synaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.

JOURNAL/nrgr/04.03/01300535-202606000-00059/figure1/v/2026-02-11T151048Z/r/image-tiff The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades. In this study, we performed single-cell RNA sequencing to investigate the cellular composition of the ependymal surface of the adult mouse forebrain using whole mounts of lateral walls of lateral ventricles. We identified 12 different cell subtypes in the ependymal surface. Immunocytochemical analyses revealed that CD133 + multi-ciliated cells comprised 67.6% of ependymal cells, while the remaining 32.4% were CD133 - . CD133 + ependymal cells can be further classified into FOXJ1 + /SOX2 + /ACTA2 + cells, FLT1 + /CD31 + /CLDN5 + endothelial-like cells, and PDGFRB + /VTN + /NG2 + pericyte-like cells, as well as endothelial-pericyte-like cells and Foxj1+ endothelial-like cells. CD133 - ependymal cells can be further divided into endothelial-like cells, Foxj1+ ependymal cells, Foxj1+ endothelial-like cells, pericyte-like cells, endothelial-pericyte-like cells, VIM + cells, and cells negative for all of these markers. This comprehensive profiling confirms the heterogeneity of the ependymal surface in the adult mouse forebrain. Debate regarding whether adult ependymal cells contain neural stem cells has arisen because different researchers have examined different populations of ependymal cells. Our study provides a new perspective for investigation of clinical endogenous neural stem cells, ultimately paving the way for stem cell therapies in neurological diseases.