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    15 February 2025, Volume 20 Issue 2 Previous Issue    Next Issue
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    A new horizon for neuroscience: terahertz biotechnology in brain research
    Zhengping Pu, Yu Wu, Zhongjie Zhu, Hongwei Zhao, Donghong Cui
    2024, 20 (2):  309-325.  doi: 10.4103/NRR.NRR-D-23-00872
    Abstract ( 242 )   PDF (5738KB) ( 123 )   Save
    Terahertz biotechnology has been increasingly applied in various biomedical fields and has especially shown great potential for application in brain sciences. In this article, we review the development of terahertz biotechnology and its applications in the field of neuropsychiatry. Available evidence indicates promising prospects for the use of terahertz spectroscopy and terahertz imaging techniques in the diagnosis of amyloid disease, cerebrovascular disease, glioma, psychiatric disease, traumatic brain injury, and myelin deficit. In vitro and animal experiments have also demonstrated the potential therapeutic value of terahertz technology in some neuropsychiatric diseases. Although the precise underlying mechanism of the interactions between terahertz electromagnetic waves and the biosystem is not yet fully understood, the research progress in this field shows great potential for biomedical noninvasive diagnostic and therapeutic applications. However, the biosafety of terahertz radiation requires further exploration regarding its two-sided efficacy in practical applications. This review demonstrates that terahertz biotechnology has the potential to be a promising method in the field of neuropsychiatry based on its unique advantages.
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    Repetitive transcranial magnetic stimulation in Alzheimer’s disease: effects on neural and synaptic rehabilitation
    Yi Ji, Chaoyi Yang, Xuerui Pang, Yibing Yan, Yue Wu, Zhi Geng, Wenjie Hu, Panpan Hu, Xingqi Wu, Kai Wang
    2024, 20 (2):  326-342.  doi: 10.4103/NRR.NRR-D-23-01201
    Abstract ( 202 )   PDF (1141KB) ( 216 )   Save
    Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis. The Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized, thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life, leaving patients incapacitated. Repetitive transcranial magnetic stimulation is a cost-effective, neuro-modulatory technique used for multiple neurological conditions. Over the past two decades, it has been widely used to predict cognitive decline; identify pathophysiological markers; promote neuroplasticity; and assess brain excitability, plasticity, and connectivity. It has also been applied to patients with dementia, because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult. However, its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies. This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment, evaluate its effects on synaptic plasticity, and identify the associated mechanisms. This review essentially focuses on changes in the pathology, amyloidogenesis, and clearance pathways, given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s disease. Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription, which are closely related to the neural regeneration process, are also highlighted. Finally, we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation, with the aim to highlight future directions for better clinical translations.
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    Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans
    Ana Milena Silva Olaya, Fernanda Martins Almeida, Ana Maria Blanco Martinez, Suelen Adriani Marques
    2024, 20 (2):  343-353.  doi: 10.4103/NRR.NRR-D-23-01752
    Abstract ( 50 )   PDF (8222KB) ( 25 )   Save
    Spinal cord injury results in the loss of sensory, motor, and autonomic functions, which almost always produces permanent physical disability. Thus, in the search for more effective treatments than those already applied for years, which are not entirely efficient, researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach, seeking to promote neuronal recovery after spinal cord injury. Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and, consequently, boosting functional recovery. Although the majority of experimental research has been conducted in rodents, there is increasing recognition of the importance, and need, of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans. This article is a literature review from databases (PubMed, Science Direct, Elsevier, Scielo, Redalyc, Cochrane, and NCBI) from 10 years ago to date, using keywords (spinal cord injury, cell therapy, non-human primates, humans, and bioengineering in spinal cord injury). From 110 retrieved articles, after two selection rounds based on inclusion and exclusion criteria, 21 articles were analyzed. Thus, this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans, aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.
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    Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders: progress of experimental models based on disease pathogenesis
    Li Xu, Huiming Xu, Changyong Tang
    2024, 20 (2):  354-365.  doi: 10.4103/NRR.NRR-D-23-01325
    Abstract ( 116 )   PDF (2093KB) ( 132 )   Save
    Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction. To date, no effective treatment exists as the exact causative mechanism remains unknown. Therefore, experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets. Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4, which is highly expressed on the membrane of astrocyte endfeet, most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes. These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders, such as aquaporin-4 loss, astrocytopathy, granulocyte and macrophage infiltration, complement activation, demyelination, and neuronal loss; however, they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders. In this review, we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro, ex vivo, and in vivo for neuromyelitis optica spectrum disorders, suggest potential pathogenic mechanisms for further investigation, and provide guidance on experimental model choices. In addition, this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders, offering further therapeutic targets and a theoretical basis for clinical trials.
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    Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy
    Samuel Abokyi, Dennis Yan-yin Tse
    2024, 20 (2):  366-377.  doi: 10.4103/NRR.NRR-D-23-02033
    Abstract ( 59 )   PDF (1397KB) ( 32 )   Save
    Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrientsensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
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    Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets
    Jingxiang Zhang, Xia Sheng, Quanju Ding, Yujun Wang, Jiwei Zhao, Jingfa Zhang
    2024, 20 (2):  378-393.  doi: 10.4103/NRR.NRR-D-23-01642
    Abstract ( 196 )   PDF (3554KB) ( 228 )   Save
    Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular agerelated macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-β, transforming growth factor-β signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70–Toll-like receptors 2/4–interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.
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    Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination
    Josep Tomàs, Víctor Cilleros-Mañé, Laia Just-Borràs, Marta Balanyà-Segura, Aleksandra Polishchuk, Laura Nadal, Marta Tomàs, Carolina Silvera-Simón, Manel M. Santafé, Maria A. Lanuza
    2024, 20 (2):  394-401.  doi: 10.4103/1673-5374.391314
    Abstract ( 73 )   PDF (912KB) ( 27 )   Save
    During the development of the nervous system, there is an overproduction of neurons and synapses. Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening. We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosinrelated kinase B receptor neurotrophic retrograde pathway, at the neuromuscular junction, in the axonal development and synapse elimination process versus the synapse consolidation. The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination, in relation to other molecular pathways that we and others have found to regulate this process. In particular, we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors, coupled to downstream serine-threonine protein kinases A and C (PKA and PKC) and voltage-gated calcium channels, at different nerve endings in developmental competition. The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site, influence each other, and require careful studies to individualize the mechanisms of specific endings. We describe an activity-dependent balance (related to the extent of transmitter release) between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals. The downstream displacement of the PKA/PKC activity ratio to lower values, both in competing nerve terminals and at postsynaptic sites, plays a relevant role in controlling the elimination of supernumerary synapses. Finally, calcium entry through L- and P/Q- subtypes of voltagegated calcium channels (both channels are present, together with the N-type channel in developing nerve terminals) contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination (the weakest in acetylcholine release and those that have already become silent). The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development. Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
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    The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia
    Xiaorong Zhang, Zhiying Chen, Yinyi Xiong, Qin Zhou, Ling-Qiang Zhu, Dan Liu
    2024, 20 (2):  402-415.  doi: 10.4103/NRR.NRR-D-23-01353
    Abstract ( 107 )   PDF (3692KB) ( 44 )   Save
    With an increase in global aging, the number of people affected by cerebrovascular diseases is also increasing, and the incidence of vascular dementia—closely related to cerebrovascular risk—is increasing at an epidemic rate. However, few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients. Similarly in Alzheimer’s disease and other neurological disorders, synaptic dysfunction is recognized as the main reason for cognitive decline. Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system. Recently, nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia. This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction, neuroinflammation, oxidative stress, and blood–brain barrier dysfunction that underlie the progress of vascular dementia. Additionally, we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.
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    Interleukin 1β receptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1
    Roberto Piacentini, Claudio Grassi
    2024, 20 (2):  416-423.  doi: 10.4103/NRR.NRR-D-23-01690
    Abstract ( 69 )   PDF (720KB) ( 39 )   Save
    Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease. However, the molecular mechanisms underlying this association are not completely understood. Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role. Here, we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain, highlighting the role of interleukins and, in particular, interleukin 1β as a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.
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    Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer’s disease
    Mengqi Hao, Jianjian Chu, Tinglin Zhang, Tong Yin, Yuankai Gu, Wendanqi Liang, Wenbo Ji, Jianhua Zhuang, Yan Liu, Jie Gao, You Yin
    2024, 20 (2):  424-439.  doi: 10.4103/NRR.NRR-D-23-01736
    Abstract ( 125 )   PDF (8022KB) ( 64 )   Save
    Alzheimer’s disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer’s disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease. Currently, the efficacy of drugs in treating Alzheimer’s disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer’s disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease. The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.
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    P2Y1 receptor in Alzheimer’s disease
    Shan Luo, Yifei Wang, Tatsuhiro Hisatsune
    2024, 20 (2):  440-453.  doi: 10.4103/NRR.NRR-D-23-02103
    Abstract ( 64 )   PDF (11397KB) ( 15 )   Save
    Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades. However, existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic, necessitating the exploration of alternative therapeutic strategies. Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients, with dysregulated astrocytic purinergic receptors, particularly the P2Y1 receptor, all of which constitute the pathophysiology of Alzheimer’s disease. These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease. This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation, thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
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    Microglia: a promising therapeutic target in spinal cord injury
    Xiaowei Zha, Guoli Zheng, Thomas Skutella, Karl Kiening, Andreas Unterberg, Alexander Younsi
    2024, 20 (2):  454-463.  doi: 10.4103/NRR.NRR-D-23-02044
    Abstract ( 134 )   PDF (1986KB) ( 87 )   Save
    Microglia are present throughout the central nervous system and are vital in neural repair, nutrition, phagocytosis, immunological regulation, and maintaining neuronal function. In a healthy spinal cord, microglia are accountable for immune surveillance, however, when a spinal cord injury occurs, the microenvironment drastically changes, leading to glial scars and failed axonal regeneration. In this context, microglia vary their gene and protein expression during activation, and proliferation in reaction to the injury, influencing injury responses both favorably and unfavorably. A dynamic and multifaceted injury response is mediated by microglia, which interact directly with neurons, astrocytes, oligodendrocytes, and neural stem/progenitor cells. Despite a clear understanding of their essential nature and origin, the mechanisms of action and new functions of microglia in spinal cord injury require extensive research. This review summarizes current studies on microglial genesis, physiological function, and pathological state, highlights their crucial roles in spinal cord injury, and proposes microglia as a therapeutic target.
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    From mice to humans: a need for comparable results in mammalian neuroplasticity
    Marco Ghibaudi, Enrica Boda, Luca Bonfanti
    2024, 20 (2):  464-466.  doi: 10.4103/NRR.NRR-D-24-00143
    Abstract ( 70 )   PDF (1499KB) ( 19 )   Save
    Brain plasticity—A universal tool with many variations: The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information (> 80,000 results in PubMed). Overall, different types of plasticity, including stem cell-driven genesis of new neurons (adult neurogenesis), cells in arrested maturation (dormant neurons), neuro-glial and synaptic plasticity, can coexist and contribute to grant plastic changes in the brain, from a cellular to system level (Benedetti and Couillard-Despres, 2022; Bonfanti et al., 2023). Most of the current knowledge is based on laboratory rodents and largely deals with cellular and molecular mechanisms aimed at exploiting a potential for brain repair. Comparative approaches have also been used, spanning from simple organisms (e.g., drosophila, zebrafish) to the direct study of human brains (either on postmortem tissue or through non-invasive imaging). The finding of common aspects in the entire animal world leads to consider neural plasticity as a shared biological tool to allow structural and functional changes as an adaptive mechanism. Conversely, due to adaptation itself, different types of plasticity emerged in animal groups living in widely different ecological niches (Barker et al., 2011). Consequently, the occurrence of the main types of plastic changes (i.e., synaptic plasticity, adult neurogenesis, and immature, or “dormant” neurons; Benedetti and Couillard-Despres, 2022; Bonfanti et al., 2023) can remarkably vary depending on the animal species or age considered, regarding their anatomical location, spatial extension, and rate (Paredes et al., 2016; La Rosa et al., 2020; Figure 1A). For instance, the genesis of new neurons is abundant, topographically widespread, and consistent through the lifespan in fish, whereas it appears quite reduced in mammals, both in space and time (Bonfanti, 2011). Another important difference between non-mammalian and mammalian brain plasticity concerns its ultimate role, which encompasses striking regenerative processes allowing brain repair in the former, while being mostly aimed at refining the neural circuits through postnatal brain development in the latter (Bonfanti, 2011). Though the different types of brain plasticity can be found in all species, comparative research started to reveal significant variation among mammals, particularly concerning different types of neurogenic processes (with and without division; Benedetti and Couillard-Despres, 2022) that can show either high or low rates depending on brain size, gyrencephaly, and longevity of the species considered (Bonfanti et al., 2023). These interspecies variations underline the notion that plasticity is not a brain function, rather a tool that can be used to perform remarkably differing functions among animal species (Barker et al., 2011). There are multiple explanations for the adaptive significance of adult neurogenesis and how particular ecological needs and evolutionary pathways have directed its function in each animal group. These adaptive processes are at the basis of a trade-off in different types of plasticity, determining a high interspecies heterogeneity that must be known for the correct translation of experimental results obtained in laboratory rodents (Bonfanti et al., 2023). In summary, besides data indicating evolutionary conservation of cellular/molecular mechanisms and local circuit connectivity motifs in mice and humans, the existence of remarkable differences in neuroanatomy, global connectivity, and, particularly, neurogenic plasticity, increases the need for multispecies comparative studies (Bonfanti et al., 2023; Figure 1A). Yet, such kind of approach, in addition to obvious technical and ethical difficulties, entails the problem of obtaining comparable results.
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    Astrocytes integrate time and space
    Justin Lines
    2024, 20 (2):  467-468.  doi: 10.4103/NRR.NRR-D-24-00005
    Abstract ( 60 )   PDF (664KB) ( 30 )   Save
    Astrocytes read and react to synaptic transmission through tripartite synapses, where the binding of neurotransmitters onto astrocytic receptors triggers an increase in intracellular calcium. Recent investigations have revealed that astrocytes exhibit two distinct states of intracellular calcium activity: (1) graded subcellular localized clusters with independently active microdomains, likely influenced by nearby synaptic events, and (2) whole-cell astrocyte calcium surges, believed to result from the coordinated activation of multiple synapses. Notably, astrocyte calcium responses are not solely graded; instead, a spatial threshold of intracellular calcium activity can be overcome to elicit an astrocyte calcium surge. Together these calcium responses, in turn, initiate downstream signaling pathways capable of modifying synaptic communication and overall network activity. In summary, astrocytes can function as integrators of local synaptic events, actively contributing to information processing within the brain.
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    A lead role for a “secondary” axonal injury response
    Melissa A. Rudy, Trent A. Watkins
    2024, 20 (2):  469-470.  doi: 10.4103/NRR.NRR-D-23-02070
    Abstract ( 75 )   PDF (775KB) ( 32 )   Save
    Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system repair. However, this stress response drives neuronal apoptosis in non-regenerative environments. This duality presents a quandary for the development of therapeutic interventions: manipulating stress signaling to enhance recovery of damaged neurons risks accelerating neurodegeneration or restricting regenerative potential. This dichotomy is well illustrated by the fates of retinal ganglion cells (RGCs) following optic nerve crush. In this central nervous system injury model, disruption of a stress-activated MAP kinase (MAPK) cascade blocks the extensive apoptosis of RGCs that occurs in wild-type mice (Watkins et al., 2013; Welsbie et al., 2017). However, targeting that pathway also limits the efficacy of interventions, such as knockout of the tumor suppressor PTEN, that allow for modest RGC axon regeneration (Watkins et al., 2013). Blocking a parallel injury-response pathway, the integrated stress response (ISR), partially protects injured RGCs, but its contribution to transcription and axon regeneration has, until recently, remained obscure (Yang et al., 2016; Larhammar et al., 2017). Our investigations have revealed that this “secondary” arm plays an unexpectedly comprehensive role in the injury response, controlling not only neurodegeneration but also axon regenerative potential (Somasundaram et al., 2023). These findings suggest that the coordinated action of these parallel stress pathways is required for both repair and apoptosis, underscoring the need for greater understanding of the additional mechanisms that determine which of these outcomes prevails.
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    Search for microglia-specific peptides: advances in the discovery toolbox
    Ivan Sarabia, Kyle M. Koss
    2024, 20 (2):  471-472.  doi: 10.4103/NRR.NRR-D-24-00151
    Abstract ( 42 )   PDF (6269KB) ( 20 )   Save
    Uncontrolled and chronic inflammatory states in the central nervous system (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan- rich scar tissue. This gliotic scar blocks significant portions of healthy axonal networking, preventing regeneration. Since most neuroinflammation is exclusively based on the responses of said microglia, their phenotypes are suggested to follow those of macrophages; M1 and M2 are opposites of pro- and anti-inflammation. However, microglial phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. More recent work has suggested that microglia also undergo a priming phenotype as a response to unresolved or sustained chronic inflammation, which is thought to be associated with neurodegenerative and neuropsychiatric disorders. Several research groups have recently focused on peptide discovery to target these phenotypes, find their novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. A handful of peptides targeting unique microglia phenotypes have emerged from discovery experiments. With the hope of mediating deleterious cell-killing behaviors or promoting beneficial outcomes in neuroinflammation, a great need for said peptide discovery exists. This article highlights the benefits, challenges, and potential resolutions in discovering peptide and peptide tools for microglia physiology and pathophysiology. A summary of studies is shown in Table 1 and an example is shown in Figure 1.
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    Exploring the novel role of oligodendrocyte precursor cells in phagocytosis: beyond myelinogenesis
    Gen Hamanaka, Ken Arai
    2024, 20 (2):  473-474.  doi: 10.4103/NRR.NRR-D-24-00062
    Abstract ( 90 )   PDF (513KB) ( 51 )   Save
    Roles of oligodendrocyte precursor cells in the central nervous system: Oligodendrocyte precursor cells (OPCs) have long been recognized for their critical role as precursors to oligodendrocytes, the primary myelin- producing cells. As precursors, OPCs mature and differentiate into oligodendrocytes, which contribute significantly to the formation of myelin sheaths around axons. This myelination, which is critical for the conduction of salutatory nerve impulses in the cerebral white matter, underscores the classical role of oligodendrocytes in central nervous system (CNS) functionality. Importantly, because oligodendrocytes are differentiated cells that cannot proliferate, OPCs are responsible for increasing and maintaining the number of oligodendrocytes. In addition, a subset of OPCs is known to remain in their precursor state even in the adult brain. In response to developmental cues or brain injury, OPCs exhibit remarkable plasticity – migrating to specific brain regions, proliferating, and differentiating into mature, functional oligodendrocytes.
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    Calcium channels caught in peripheral glia’s tug-of-war on axon regeneration in Drosophila
    Jackson Powell, Tobias Steinschaden, Rose Horowitz, Yuanquan Song
    2024, 20 (2):  475-476.  doi: 10.4103/NRR.NRR-D-23-02049
    Abstract ( 66 )   PDF (472KB) ( 42 )   Save
    Neural damage or degeneration is at the crux of many diseases, and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration. Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate, and the combination of these factors results in the great regenerative capacity of the peripheral nervous system (PNS) and the poor regenerative capacity of the central nervous system (CNS) following injury. At the core of a neuron’s function is its ability to relay electrochemical signals, and a neuron’s excitability is a key factor in its ability to regenerate. Recent works have focused on the changes in neuronal electrophysiological properties, firing patterns, and ion flux after injury, which differentially activate signaling pathways at the core of regeneration. The role of glia in neuron regeneration has long been studied, but new and expanded signaling pathways are still being discovered. Recent work has demonstrated the ability of glia to modulate neuron firing (Lezmy et al., 2021), which has overlapping implications in a regenerative context. The neuron–glia interactions, and their effects on excitability and pathway activation, are highly context-dependent, but mark an essential frontier in our understanding of neural regeneration and related therapeutics (Figure 1). Here, we will discuss our recent publication and other exciting works in the field.
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    Gamma oscillations and their role in orchestrating balance and communication following stroke
    Montana Samantzis, Cong Wang, Matilde Balbi
    2024, 20 (2):  477-478.  doi: 10.4103/NRR.NRR-D-24-00127
    Abstract ( 68 )   PDF (841KB) ( 15 )   Save
    Induced brain oscillations in the gamma range have recently garnered attention due to their reported neuroprotective effects in the treatment of Alzheimer’s disease. This method differs from pharmacological approaches by tapping into the neuronal population dynamics that underlie the homeostatic processes in the brain that are crucial for the recovery of function. Recently, induced gamma-range oscillations have been used to improve cerebral blood flow, motor function, and synaptic plasticity in a mouse model of focal stroke, highlighting the broad potential of recruiting intrinsic recovery processes for the treatment of neurological conditions. Addressing open questions, such as the frequency specificity of the benefits, will shed light on the intrinsic processes involved and allow clinicians to optimize recovery after stroke.
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    A-kinase anchoring protein–mediated compartmentalization of pro-survival signaling in the retina
    Joanna Mackiewicz, Tomasz Boczek
    2024, 20 (2):  479-480.  doi: 10.4103/NRR.NRR-D-24-00168
    Abstract ( 32 )   PDF (2239KB) ( 11 )   Save
    The retina plays a fundamental role in the process of vision, serving as the primary interface between external visual stimuli and the central nervous system. Because the retina is exposed to a variety of environmental stresses and deleterious insults, it is susceptible to a spectrum of pathological conditions that can detrimentally affect vision. This often leads to irreversible vision loss due to the injury of specific cell types. For instance, inherited retinal degeneration and age- related macular degeneration can lead to the death of photoreceptors, while conditions like glaucoma and optic nerve injury can result in the loss of ganglion cells. The precise pathological mechanisms driving retinal degeneration remain largely elusive, although research utilizing mouse models suggests that disruptions in intracellular signal transduction pathways may play a pivotal role. Signaling pathways within the retina orchestrate various aspects of retinal physiology, including phototransduction, synaptic transmission, and neuronal survival. Among these pathways, cyclic adenosine monophosphate (cAMP) signaling emerges as a central mechanism for coordinating pro-survival responses to a variety of insults.
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    Bioelectronic medicine in modulation of cortical spreading depolarization and beyond
    Khaled Alok, Timothy G. White, Chunyan Li
    2024, 20 (2):  481-482.  doi: 10.4103/NRR.NRR-D-23-02059
    Abstract ( 79 )   PDF (474KB) ( 19 )   Save
    Bioelectronic interventions, specifically trigeminal nerve stimulation (TNS), have attracted considerable attention in conditions where cortical spreading depolarizations (CSDs) accompanied by compromised cerebral perfusion may exacerbate neurological damage. While pharmacological interventions have demonstrated initial potential in addressing CSDs, a standardized treatment approach has not yet been established. The objective of this perspective is to explore emerging bioelectronic methodologies for addressing CSDs, particularly emphasizing TNS, and to underscore TNS’s capacity to enhance neurovascular coupling and cerebral perfusion.
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    Sex-dependent alterations in extracellular vesicles linking chronic spinal cord injury to brain neuroinflammation and neurodegeneration
    Yun Li, Junfang Wu
    2024, 20 (2):  483-484.  doi: 10.4103/NRR.NRR-D-24-00189
    Abstract ( 73 )   PDF (1158KB) ( 24 )   Save
    Traumatic spinal cord injury (SCI) is a devastating exogenous injury with long-lasting consequences and a leading cause of death and disability worldwide. Advances in assistive technology, rehabilitative interventions, and the ability to identify and intervene in secondary conditions have significantly increased the long-term survival rate of SCI patients, with some people even living well into their seventh or eighth decade. These survival changes have led neurotrauma researchers to examine how SCI interacts with brain aging. Public health and epidemiological data showed that patients with long-term SCI can have a lower life expectancy and quality of life, along with a higher risk of comorbidities and complications. Although extensive effort has been spent on promoting the recovery of locomotor and sensory functions, little research has focused on pathophysiological changes in the brain. One of the long-term consequences of SCI is neuropsychological impairment, which includes deficits in memory, executive functions, attention span, processing speed, and learning abilities. Clinical studies show that SCI patients are more likely to be diagnosed with depression, anxiety, dementia, and other neurological disorders of the brain (Craig et al., 2017; Sachdeva et al., 2018; Distel et al., 2020). In fact, one study showed that SCI patients are 13 times more likely to show cognitive and emotional deficits (Craig et al., 2017). These reported cognitive impairments and mood disorders will not only compromise SCI patients’ quality of life and prognosis but also have deleterious effects on rehabilitation and recovery. However, despite these serious implications, few studies have focused on the underlying mechanisms of brain dysfunctions following SCI.
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    Movement analysis in the diagnosis and management of Parkinson’s disease
    Johannes Burtscher, Nicolas Bourdillon, Jules M. Janssen Daalen, Aurélien Patoz, Julien F. Bally, Martin Kopp, Davide Malatesta, Bastiaan R. Bloem
    2024, 20 (2):  485-486.  doi: 10.4103/NRR.NRR-D-24-00207
    Abstract ( 69 )   PDF (1150KB) ( 54 )   Save
    Challenges in the diagnosis and treatment of Parkinson’s disease: Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disease, at first sight primarily characterized by motor symptoms, although non-motor symptoms also constitute a major part of the overall phenotype. Clinically, this disease cannot be diagnosed reliably until a large part of the vulnerable dopaminergic neurons has been irretrievably lost, and the disease progresses inexorably. New biological criteria for PD have been proposed recently and might eventually improve early diagnosis, but they require further validation, and their use will initially be restricted to a research environment (Darweesh et al., 2024). Today, the clinical diagnosis of PD is based primarily on subjective criteria and is impeded by high intra- and interindividual variability. In early disease stages, the differentiation from other diseases can be challenging, hampering the timely selection of the best treatment options. While some of the cardinal motor symptoms associated with PD can be treated effectively in the early stages, disease-modifying interventions and treatments for debilitating non-motor symptoms remain elusive. The many new (primarily pharmacological) strategies currently evaluated for PD are often optimizations of existing approaches (e.g., variations of treatments with dopamine precursors or dopamine receptor agonists) or belong to the class of the highly debated anti-protein aggregation treatments. Breakthrough strategies to reliably halt or slow down PD progression might be just around the corner but the history of unsuccessful translations of promising novel preclinical treatments for PD during the last decades warrants a certain amount of skepticism.
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    From text to image: challenges in integrating vision into ChatGPT for medical image interpretation
    Shunsuke Koga, Wei Du
    2024, 20 (2):  487-488.  doi: 10.4103/NRR.NRR-D-24-00165
    Abstract ( 57 )   PDF (336KB) ( 16 )   Save
    Large language models (LLMs), such as ChatGPT developed by OpenAI, represent a significant advancement in artificial intelligence (AI), designed to understand, generate, and interpret human language by analyzing extensive text data. Their potential integration into clinical settings offers a promising avenue that could transform clinical diagnosis and decision-making processes in the future (Thirunavukarasu et al., 2023). This article aims to provide an in-depth analysis of LLMs’ current and potential impact on clinical practices. Their ability to generate differential diagnosis lists underscores their potential as invaluable tools in medical practice and education (Hirosawa et al., 2023; Koga et al., 2023). However, integrating LLMs into clinical practice requires careful consideration of their limitations and challenges to ensure their effective and responsible application (Thirunavukarasu et al., 2023).
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    Women in visual neural regeneration research
    Tonia S. Rex, David J. Calkins
    2024, 20 (2):  489-490.  doi: 10.4103/NRR.NRR-D-24-00125
    Abstract ( 47 )   PDF (569KB) ( 23 )   Save
    The year 2024 marks the 60th anniversary of Title IX and 25 years since the New York Times revealed bias against female faculty members at the Massachusetts Institute of Technology. We take an opportunity here to examine the state of gender bias in a relatively new yet already prominent field, neural regeneration in the visual system, for which there is a well-defined context useful for this purpose. The National Eye Institute (NEI) provided the first round of research funding for its Audacious Goals Initiative (AGI) on visual neural regeneration in 2013 and the last round in 2021. Therefore, we focus on this timespan. Data sources included PubMed, the National Science Foundation (NSF), the NEI, the Blue Ridge Institute for Medical Research and data from the major professional organization for eye and vision research, the Association for Research in Vision and Ophthalmology (ARVO).
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    Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke
    Shuai Feng, Juanji Li, Tingting Liu, Shiqi Huang, Xiangliang Chen, Shen Liu, Junshan Zhou, Hongdong Zhao, Ye Hong
    2024, 20 (2):  491-502.  doi: 10.4103/NRR.NRR-D-23-01263
    Abstract ( 81 )   PDF (18456KB) ( 28 )   Save
    Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen–glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen–glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
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    A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury
    Qi Liu, Jianye Xie, Runxue Zhou, Jin Deng, Weihong Nie, Shuwei Sun, Haiping Wang, Chunying Shi
    2024, 20 (2):  503-517.  doi: 10.4103/NRR.NRR-D-23-01322
    Abstract ( 106 )   PDF (7767KB) ( 59 )   Save
    Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI (QK) are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases. However, conventional topical drug delivery often results in a burst release of the drug, leading to transient retention (inefficacy) and undesirable diffusion (toxicity) in vivo. Therefore, a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke. Matrix metalloproteinase-2 (MMP-2) is gradually upregulated after cerebral ischemia. Herein, vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG (TIMP) and customizable peptide amphiphilic (PA) molecules to construct nanofiber hydrogel PA-TIMP-QK. PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro. The results indicated that PA-TIMP-QK promoted neuronal survival, restored local blood circulation, reduced blood-brain barrier permeability, and restored motor function. These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
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    Human-induced pluripotent stem cell–derived neural stem cell exosomes improve blood–brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis
    Conglin Wang, Fangyuan Cheng, Zhaoli Han, Bo Yan, Pan Liao, Zhenyu Yin, Xintong Ge, Dai Li, Rongrong Zhong, Qiang Liu, Fanglian Chen, Ping Lei
    2024, 20 (2):  518-532.  doi: 10.4103/NRR.NRR-D-23-01889
    Abstract ( 120 )   PDF (6348KB) ( 71 )   Save

    Cerebral edema caused by blood–brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell–derived neural stem cell exosomes (hiPSC–NSC–Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC–NSC–Exos on blood–brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC–NSC–Exos mitigated neurological deficits, enhanced blood–brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC–NSC–Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post–intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC–NSC–Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood–brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood–brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

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    Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice
    Yanli Zhang, Tian Li, Jie Miao, Zhina Zhang, Mingxuan Yang, Zhuoran Wang, Bo Yang, Jiawei Zhang, Haiting Li, Qiang Su, Junhong Guo
    2024, 20 (2):  533-547.  doi: 10.4103/NRR.NRR-D-23-01525
    Abstract ( 95 )   PDF (13640KB) ( 25 )   Save
    In patients with Alzheimer’s disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer’s disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease (Aβ1–42–treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-β in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of β-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
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    Transforming growth factor-beta 1 enhances discharge activity of cortical neurons
    Zhihui Ren, Tian Li, Xueer Liu, Zelin Zhang, Xiaoxuan Chen, Weiqiang Chen, Kangsheng Li, Jiangtao Sheng
    2024, 20 (2):  548-556.  doi: 10.4103/NRR.NRR-D-23-00756
    Abstract ( 77 )   PDF (2916KB) ( 32 )   Save
    Transforming growth factor-beta 1 (TGF-β1) has been extensively studied for its pleiotropic effects on central nervous system diseases. The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved. Voltage-gated sodium channels (VGSCs) are essential ion channels for the generation of action potentials in neurons, and are involved in various neuroexcitation-related diseases. However, the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear. In this study, we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice. We found that TGF-β1 increased VGSC current density in a dose- and time-dependent manner, which was attributable to the upregulation of Nav1.3 expression. Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase (PD98059), p38 mitogen-activated protein kinase (SB203580), and Jun NH2-terminal kinase 1/2 inhibitor (SP600125). Interestingly, TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons. These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2–JNK–MAPK pathway, which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions. Thus, this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.
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    Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury
    Jiewen Chen, Xiaolin Zeng, Le Wang, Wenwu Zhang, Gang Li, Xing Cheng, Peiqiang Su, Yong Wan, Xiang Li
    2024, 20 (2):  557-573.  doi: 10.4103/NRR.NRR-D-23-01130
    Abstract ( 116 )   PDF (13224KB) ( 62 )   Save
    Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury. Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction. However, the mechanisms involved remain unclear. In this study, we found that after spinal cord injury, resting microglia (M0) were polarized into pro-inflammatory phenotypes (MG1 and MG3), while resting astrocytes were polarized into reactive and scar-forming phenotypes. The expression of growth arrest-specific 6 (Gas6) and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury. In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia, and even inhibited the cross-regulation between them. We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway. This, in turn, inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways. In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord, thereby promoting tissue repair and motor function recovery. Overall, Gas6 may play a role in the treatment of spinal cord injury. It can inhibit the inflammatory pathway of microglia and polarization of astrocytes, attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment, and thereby alleviate local inflammation and reduce scar formation in the spinal cord.
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    Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson’s disease
    Olivier Kerdiles, Méryl-Farelle Oye Mintsa Mi-mba, Katherine Coulombe, Cyntia Tremblay, Vincent Émond, Martine Saint-Pierre, Clémence Rouxel, Line Berthiaume, Pierre Julien, Francesca Cicchetti, Frédéric Calon
    2024, 20 (2):  574-586.  doi: 10.4103/NRR.NRR-D-23-00595
    Abstract ( 53 )   PDF (3939KB) ( 15 )   Save
    There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson’s disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.
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    Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury
    Tong Li, Hui-Min Xing, Hai-Dong Qian, Qiao Gao, Sheng-Lan Xu, Hua Ma, Zai-Long Chi
    2024, 20 (2):  587-597.  doi: 10.4103/NRR.NRR-D-23-01414
    Abstract ( 108 )   PDF (8203KB) ( 83 )   Save
    Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
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    Photobiomodulation: a novel approach to promote trans-differentiation of adipose-derived stem cells into neuronal-like cells
    Daniella Da Silva, Madeleen Jansen van Rensburg, Anine Crous, Heidi Abrahamse
    2024, 20 (2):  598-608.  doi: 10.4103/NRR.NRR-D-23-01219
    Abstract ( 142 )   PDF (11903KB) ( 32 )   Save
    Photobiomodulation, originally used red and near-infrared lasers, can alter cellular metabolism. It has been demonstrated that the visible spectrum at 451–540 nm does not necessarily increase cell proliferation, near-infrared light promotes adipose stem cell proliferation and affects adipose stem cell migration, which is necessary for the cells homing to the site of injury. In this in vitro study, we explored the potential of adipose-derived stem cells to differentiate into neurons for future translational regenerative treatments in neurodegenerative disorders and brain injuries. We investigated the effects of various biological and chemical inducers on trans-differentiation and evaluated the impact of photobiomodulation using 825 nm near-infrared and 525 nm green laser light at 5 J/cm2. As adipose-derived stem cells can be used in autologous grafting and photobiomodulation has been shown to have biostimulatory effects. Our findings reveal that adipose-derived stem cells can indeed trans-differentiate into neuronal cells when exposed to inducers, with pre-induced cells exhibiting higher rates of proliferation and trans-differentiation compared with the control group. Interestingly, green laser light stimulation led to notable morphological changes indicative of enhanced trans-differentiation, while near-infrared photobiomodulation notably increased the expression of neuronal markers. Through biochemical analysis and enzyme-linked immunosorbent assays, we observed marked improvements in viability, proliferation, membrane permeability, and mitochondrial membrane potential, as well as increased protein levels of neuron-specific enolase and ciliary neurotrophic factor. Overall, our results demonstrate the efficacy of photobiomodulation in enhancing the trans-differentiation ability of adipose-derived stem cells, offering promising prospects for their use in regenerative medicine for neurodegenerative disorders and brain injuries.
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