Cellular and Molecular Neurobiology最新文献

Intracranial infections remain a major neurocritical care challenge, causing high mortality and long-term deficits despite advances in antimicrobials, imaging, and intensive care. Because bacterial, viral, fungal, and parasitic pathogens trigger distinct immune pathways, they produce characteristic CSF leukocyte patterns shaped by pathogen sensing, endothelial adhesion molecule expression, chemokine gradients, and leukocyte migration across CNS barriers. Pleocytosis therefore reflects PRR activation and tends toward neutrophil, lymphocyte, or monocyte-macrophage predominance. Notably, promptly distinguishing infectious encephalitis (IE) from autoimmune encephalitis (AE) is crucial. Specifically, bacterial infections usually create neutrophil-predominant CSF via IL-1β, TNF-α, and G-CSF, whereas viral infections such as HSV and VZV promote lymphocytic profiles through interferons and CXCR3 ligands. Fungal pathogens (Cryptococcus, Candida, Aspergillus) and mycobacteria often produce mixed or mononuclear pleocytosis due to chronic antigen exposure. These patterns guide therapy: bacterial infections require immediate empiric antibiotics with corticosteroids; HSV and VZV encephalitis needs urgent IV acyclovir; enteroviruses and arboviruses rely on supportive care; and fungal infections require staged antifungal therapy with monitoring of CNS penetration, organ function, and intracranial pressure. Parasitic and amoebic infections such as Naegleria fowleri demand individualized antiparasitic treatment, corticosteroids, seizure control, and intensive supportive care. Because CSF leukocytes also influence barrier integrity, neuronal survival, and glial activation, advanced profiling-combining CSF leukocyte phenotyping with cytokine and chemokine analysis-enhances differentiation between IE and AE and supports more targeted treatment. This review elucidates the role of CSF leukocytes in CNS infections, highlighting their diagnostic, mechanistic, and therapeutic significance for guiding precision neurocritical care. Pathogens in CSF create distinct leukocyte patterns via PRR-PAMP signaling and chemokine-driven trafficking. Bacteria cause neutrophil-rich IL-1β/TNF-α responses; viruses (HSV/VZV) produce lymphocyte-dominant interferon profiles; and fungal or mycobacterial infections show mixed or granulomatous patterns. These signatures affect BBB integrity and help distinguish infections from autoimmune encephalitis.

The endoplasmic reticulum protein quality control system-comprising endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and ER-phagy-serves as a crucial mechanism for maintaining protein homeostasis within the endoplasmic reticulum (ER) of eukaryotic cells. As a crucial pathway of recognition, transport, and degradation of misfolded proteins, ERAD dysfunction results in the excessive accumulation of aberrant proteins, thereby disrupting normal cellular physiology and ultimately leading to necrosis or apoptosis. It is reported that the occurrence and development of central and peripheral neurodegenerative diseases are closely related to the dysfunction of misfolded protein degradation. Many components within the ERAD pathway may play essential roles in these pathological processes. This review provides an overview of the ERAD processes, its regulatory mechanisms, and its involvement in the pathogenesis and potential treatment of neurodegenerative diseases, aiming to offer theoretical insight for future research on the specific roles of ERAD in different neurodegenerative diseases.

Ischemic stroke (IS) is one of the most common neurological diseases worldwide and is caused by the blockage of cerebral blood vessels, leading to reduced blood flow and neuronal damage. Given the limitations of existing treatments, CRISPR gene-editing technology has emerged as a promising strategy to precisely target the molecular pathways underlying IS pathophysiology. By enabling intervention in genes regulating inflammation, apoptosis, and repair, CRISPR enables more precise and effective therapies. Various CRISPR delivery systems, including viral vectors, nanocarriers, and extracellular vesicles, play crucial roles in the effective access of this tool to neural cells. Studies have shown that the use of CRISPR-Cas9 to modulate key pathogenic pathways, including those governing inflammation, oxidative stress, and cell death, can prevent neuronal damage and improve neurological function. Additionally, targeting ncRNAs and RNA methylation with CRISPR-based systems plays a role in regulating oxidative stress and stress granule formation. The use of CRISPR to modulate cell communication and organelle transfer and correct mitochondrial mutations has also been considered a neuroprotective mechanism. Despite persistent challenges in targeted and safe delivery, substantial preclinical advances, primarily in rodent models, underscore the potential for CRISPR-based therapies to transform future stroke treatment. These findings suggest that CRISPR-based strategies could evolve into precision neurotherapeutics that address root molecular pathologies, potentially complementing or surpassing current stroke interventions.

Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.

Alzheimer's disease (AD) is an evolving neurodegenerative disorder characterized by the presence of Amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), synaptic dysfunction, neuroinflammation, and decline in memory. Animal models are crucial resources for examining AD processes and evaluating potential treatments. Triple-transgenic mice (3xTg-AD) are genetically altered to overexpress tau, PSEN1, and APP, three genes linked to AD in humans. Both tau and amyloid pathologies are independently replicated in each model in an age-related, temporal sequence that mimics the pathophysiology of AD in humans. In addition to synaptic damage, neuroinflammation, and cognitive deficits, these mice develop intracellular Aβ accumulations at 3 to 4 months, extracellular plaques at 6 to 9 months, and NFTs at 12 months. Additionally, the model exhibits sex-dependent differences and non-cognitive symptoms like anxiety and depressive-like behavior. Recent study indicates its potential in evaluating immunotherapy, irradiation, nutraceuticals such resveratrol and lifestyle therapies for the decrease of Aβ, and tau deposition and improved cognition. Additionally, neuroimaging, and multi-omics analysis in 3xTg-AD mice provide useful biomarkers for disease monitoring. The limitations of 3xTg-AD mice include their shorter lifetime, sex-specific variations in disease and behavior and the inaccurate timing of symptom onset relative to humans. The pathological and behavioral characteristics of the 3xTg-AD mouse are well understood, but this review highlights its developing translational potential. Further studies highlight that how preclinical findings can be connected to human AD by utilizing multi-omics profiling, CRISPR-mediated genetic refinement, and integration with human iPSC-derived systems. Hence, the 3xTg-AD mouse is an effective and versatile model for studying AD processes as well as preclinical therapeutic approaches.

Neural damage, which could be characterized by demyelination and neuropathic pain, is a hallmark of leprosy, driven primarily by the interaction of Mycobacterium leprae with peripheral nerves, particularly Schwann cells. The role of indoleamine 2,3-dioxygenase (IDO) in neuroinflammation and neurodegeneration has been suggested; however, its precise contribution to leprosy-associated neuropathy remains poorly understood. This study aimed to determine whether variations in serum IDO activity, inferred from the kynurenine/tryptophan (Kyn/trp) ratio, could assist in distinguishing leprosy-associated neuropathy from other peripheral neuropathies. Additionally, we investigated the potential correlation between the increase in the Kyn/trp ratio and the extent of neural impairment. Based on clinical and electrophysiological evaluations, neural damage was classified into four severity types. Kyn/trp ratio was significantly higher in patients with leprosy neuropathy than in those with non-leprosy neuropathies. Moreover, we observed that patients exhibiting no sensory or motor responses have the highest IDO levels. Thus, the data presented here suggest that given the challenges in diagnosing leprosy neuropathy, IDO-1 activity may serve as a complementary diagnostic tool to help distinguish leprosy from other peripheral neuropathies.