RESUMEN
Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Modelos Animales de Enfermedad , Sistema Glinfático , Ratones Transgénicos , Oxitocina , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Oxitocina/farmacología , Oxitocina/administración & dosificación , Oxitocina/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Administración Intranasal , Linfangiogénesis/efectos de los fármacos , Masculino , Acuaporina 4/metabolismo , Acuaporina 4/genética , Humanos , Imagen por Resonancia Magnética , Meninges/metabolismo , Meninges/efectos de los fármacos , Meninges/diagnóstico por imagenRESUMEN
Several risk factors contribute to the development of Alzheimer's disease (AD), including genetics, metabolic health, cardiovascular history, and diet. It has been observed that women appear to face a higher risk of developing AD. Among the various hypotheses surrounding the gender disparity in AD, one pertains to the potential neuroprotective properties of estrogen. Compared to men, women are believed to be more susceptible to neuropathology due to the significant decline in circulating estrogen levels following menopause. Studies have shown, however, that estrogen replacement therapies in post-menopausal women do not consistently reduce the risk of AD. While menopause and estrogen levels are potential factors in the elevated incidence rates of AD among women, this review highlights the possible roles estrogen has in other pathways that may also contribute to the sex disparity observed in AD such as olfaction, sleep, and glymphatic functionality.
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Enfermedad de Alzheimer , Estrógenos , Sistema Glinfático , Sueño , Olfato , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Estrógenos/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatología , Sueño/fisiología , Olfato/fisiología , Femenino , Masculino , Factores SexualesRESUMEN
OBJECTIVE: The glymphatic system serves as a perivascular pathway that aids in clearing liquid and solute waste from the brain, thereby enhancing neurological function. Disorders in glymphatic drainage contribute to the development of vasogenic edema following cerebral ischemia, although the molecular mechanisms involved remain poorly understood. This study aims to determine whether a deficiency in dystrophin 71 (DP71) leads to aquaporin-4 (AQP4) depolarization, contributing to glymphatic dysfunction in cerebral ischemia and resulting in brain edema. METHODS: A mice model of middle cerebral artery occlusion and reperfusion was used. A fluorescence tracer was injected into the cortex and evaluated glymphatic clearance. To investigate the role of DP71 in maintaining AQP4 polarization, an adeno-associated virus with the astrocyte promoter was used to overexpress Dp71. The expression and distribution of DP71 and AQP4 were analyzed using immunoblotting, immunofluorescence, and co-immunoprecipitation techniques. The behavior ability of mice was evaluated by open field test. Open-access transcriptome sequencing data were used to analyze the functional changes of astrocytes after cerebral ischemia. MG132 was used to inhibit the ubiquitin-proteasome system. The ubiquitination of DP71 was detected by immunoblotting and co-immunoprecipitation. RESULTS: During the vasogenic edema stage following cerebral ischemia, a decline in the efflux of interstitial fluid tracer was observed. DP71 and AQP4 were co-localized and interacted with each other in the perivascular astrocyte endfeet. After cerebral ischemia, there was a notable reduction in DP71 protein expression, accompanied by AQP4 depolarization and proliferation of reactive astrocytes. Increased DP71 expression restored glymphatic drainage and reduced brain edema. AQP4 depolarization, reactive astrocyte proliferation, and the behavior of mice were improved. After cerebral ischemia, DP71 was degraded by ubiquitination, and MG132 inhibited the decrease of DP71 protein level. CONCLUSION: AQP4 depolarization after cerebral ischemia leads to glymphatic clearance disorder and aggravates cerebral edema. DP71 plays a pivotal role in regulating AQP4 polarization and consequently influences glymphatic function. Changes in DP71 expression are associated with the ubiquitin-proteasome system. This study offers a novel perspective on the pathogenesis of brain edema following cerebral ischemia.
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Acuaporina 4 , Edema Encefálico , Isquemia Encefálica , Distrofina , Sistema Glinfático , Animales , Acuaporina 4/metabolismo , Acuaporina 4/genética , Ratones , Sistema Glinfático/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Edema Encefálico/metabolismo , Distrofina/metabolismo , Distrofina/deficiencia , Masculino , Astrocitos/metabolismo , Ratones Endogámicos C57BL , Infarto de la Arteria Cerebral Media/metabolismoRESUMEN
BACKGROUND/AIM: The glioblastomas, aggressive brain tumors with a poor prognosis, have drawn interest in their interaction with the glymphatic system-an emerging brain drainage network. This review explores the relationship between glioblastomas and the glymphatic system, aiming to elucidate their impact on disease progression. The aim of the study was to address the alterations in the glymphatic system in the presence of glioblastoma, and their implications for disease pathogenesis and prognosis. MATERIALS AND METHODS: Following PRISMA guidelines, we conducted a systematic literature review, identifying studies on the glymphatic system in glioblastomas. Four high-quality studies were selected based on stringent criteria. Data extraction involved categorizing key findings, and thematic analysis uncovered recurring patterns in glymphatic alterations associated with glioblastomas. RESULTS: Out of 356 studies, four meeting the high-quality criteria were included. These studies revealed modifications in lymphatic outflow, factors contributing to glymphatic dysfunction, impediments to cerebrospinal fluid drainage, and emerging roles in glioma management. The findings allow a comprehensive understanding of alterations within the glymphatic system in the presence of glioblastoma. CONCLUSION: The glymphatic system in glioblastomas exhibits changes, including diminished lymphatic outflow, disruptions and obstacles to fluid drainage, which represent new dimensions in glioma management. These alterations affect drug delivery, immunotherapy, and imaging interpretation. Future research should prioritize elucidating molecular mechanisms, developing therapeutic strategies, optimizing drug delivery, exploring immunotherapy, and translating findings into clinical practice.
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Neoplasias Encefálicas , Glioblastoma , Sistema Glinfático , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , PronósticoRESUMEN
Alzheimer's disease (AD) is marked by the aggregation of extracellular amyloid-ß (Aß) and astrocyte dysfunction. For Aß oligomers or aggregates to be formed, there must be Aß monomers present; however, the roles of monomeric Aß (mAß) and oligomeric Aß (oAß) in astrocyte pathogenesis are poorly understood. We cultured astrocytes in a brain-mimicking three-dimensional (3D) extracellular matrix and revealed that both mAß and oAß caused astrocytic atrophy and hyper-reactivity, but showed distinct Ca2+ changes in astrocytes. This 3D culture evolved into a microfluidic glymphatics-on-chip model containing astrocytes and endothelial cells with the interstitial fluid (ISF). The glymphatics-on-chip model not only reproduced the astrocytic atrophy, hyper-reactivity, and Ca2+ changes induced by mAß and oAß, but recapitulated that the components of the dystrophin-associated complex (DAC) and aquaporin-4 (AQP4) were properly maintained by the ISF, and dysregulated by mAß and oAß. Collectively, mAß and oAß cause distinct AD pathophysiological characteristics in the astrocytes.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Astrocitos , Dispositivos Laboratorio en un Chip , Astrocitos/metabolismo , Astrocitos/patología , Astrocitos/citología , Péptidos beta-Amiloides/metabolismo , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Sistema Glinfático/metabolismo , Sistema Glinfático/patología , Calcio/metabolismo , Células Cultivadas , Acuaporina 4/metabolismoRESUMEN
Multiple sevoflurane exposures may damage the developing brain. The neuroprotective function of dexmedetomidine has been widely confirmed in animal experiments and human studies. However, the effect of dexmedetomidine on the glymphatic system has not been clearly studied. We hypothesized that dexmedetomidine could alleviate sevoflurane-induced circulatory dysfunction of the glymphatic system in young mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily, continuously for 3 days. Intraperitoneal injection of either normal saline or dexmedetomidine was administered before every anaesthesia. Meanwhile the circulatory function of glymphatic system was detected by tracer injection at P8 and P32. On P30-P32, behavior tests including open field test, novel object recognition test, and Y-maze test were conducted. Primary astrocyte cultures were established and treated with the PI3K activator 740Y-P, dexmedetomidine, and small interfering RNA (siRNA) to silence ΔFosB. We propose for the first time that multiple exposure to sevoflurane induces circulatory dysfunction of the glymphatic system in young mice. Dexmedetomidine improves the circulatory capacity of the glymphatic system in young mice following repeated exposure to sevoflurane through the PI3K/AKT/ΔFosB/AQP4 signaling pathway, and enhances their long-term learning and working memory abilities.
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Acuaporina 4 , Dexmedetomidina , Sistema Glinfático , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Sevoflurano , Transducción de Señal , Animales , Dexmedetomidina/farmacología , Sevoflurano/farmacología , Sevoflurano/efectos adversos , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Acuaporina 4/metabolismo , Acuaporina 4/genética , Transducción de Señal/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , MasculinoRESUMEN
The glymphatic system is cerebrospinal fluid-brain tissue fluid exchange flow mediated by aquaporin-4 (AQP4) on the end feet of astrocytes for a system, which is capable of rapidly removing brain metabolites and thus maintaining brain homeostasis, and is known as the central immune system. Dysfunction of the glymphatic system causes accumulation of misfolded and highly phosphorylated proteins (amyloid-ß and Tau proteins), which destabilizes the proteins, and the body's neuroinflammatory factors are altered causing aging of the immune system and leading to neurodegenerative diseases. Damage to the glymphatic system and aging share common manifestations, as well as unstudied biological mechanisms that are also linked, such as mitochondria, oxidative stress, chronic inflammation, and sleep. In this paper, we first summarize the structure, function, and research methods of the glymphatic system and the relationship between the glymphatic system and the peripheral immune system, and second, sort out and summarize the factors of the glymphatic system in removing metabolites and resolving aging-related diseases and factors affecting aging, to explore its related biological mechanisms, and moreover, to provide a new way of thinking for treating or intervening aging-related diseases.
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Envejecimiento , Sistema Glinfático , Humanos , Sistema Glinfático/fisiología , Sistema Glinfático/metabolismo , Envejecimiento/fisiología , Envejecimiento/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Acuaporina 4/metabolismoRESUMEN
The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport across the glial lamina. Fluid homeostasis and waste removal are vital for retinal function, making the ocular glymphatic fluid pathway a potential route for targeted manipulation to combat blinding ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Several lines of work investigating the bidirectional ocular glymphatic transport with varying methodologies have developed diverging mechanistic models, which has created some confusion about how ocular glymphatic transport should be defined. In this review, we provide a comprehensive summary of the current understanding of the ocular glymphatic system, aiming to address misconceptions and foster a cohesive understanding of the topic.
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Sistema Glinfático , Humanos , Sistema Glinfático/fisiología , Sistema Glinfático/metabolismo , Animales , Nervio Óptico/metabolismo , Nervio Óptico/fisiología , Retina/metabolismo , Retina/fisiología , Ojo/metabolismo , Glaucoma/metabolismo , Glaucoma/fisiopatología , Glaucoma/patologíaRESUMEN
Circadian clocks maintain diurnal rhythms of sleep-wake cycle of 24 h that regulate not only the metabolism of an organism but also many other periodical processes. There is substantial evidence that circadian regulation is impaired in Alzheimer's disease. Circadian clocks regulate many properties known to be disturbed in Alzheimer's patients, such as the integrity of the blood-brain barrier (BBB) as well as the diurnal glymphatic flow that controls waste clearance from the brain. Interestingly, an evolutionarily conserved transcription factor, that is, aryl hydrocarbon receptor (AhR), impairs the function of the core clock proteins and thus could disturb diurnal rhythmicity in the BBB. There is abundant evidence that the activation of AhR signalling inhibits the expression of the major core clock proteins, such as the brain and muscle arnt-like 1 (BMAL1), clock circadian regulator (CLOCK) and period circadian regulator 1 (PER1) in different experimental models. The expression of AhR is robustly increased in the brains of Alzheimer's patients, and protein level is enriched in astrocytes of the BBB. It seems that AhR signalling inhibits glymphatic flow since it is known that (i) activation of AhR impairs the function of the BBB, which is cooperatively interconnected with the glymphatic system in the brain, and (ii) neuroinflammation and dysbiosis of gut microbiota generate potent activators of AhR, which are able to impair glymphatic flow. I will examine current evidence indicating that activation of AhR signalling could disturb circadian functions of the BBB and impair glymphatic flow and thus be involved in the development of Alzheimer's pathology.
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Enfermedad de Alzheimer , Ritmo Circadiano , Sistema Glinfático , Receptores de Hidrocarburo de Aril , Animales , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Barrera Hematoencefálica/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Sistema Glinfático/metabolismo , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.
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Sistema Glinfático , Meninges , Sustancia Blanca , Sistema Glinfático/metabolismo , Animales , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Humanos , Masculino , Ratas , Femenino , Meninges/metabolismo , Modelos Animales de Enfermedad , Vasos Linfáticos/metabolismo , Anciano , Imagen por Resonancia Magnética/métodos , Estudios LongitudinalesRESUMEN
Advanced in vivo imaging techniques have facilitated the comprehensive visual exploration of animal biological processes, leading to groundbreaking discoveries such as the glymphatic system. However, current limitations of macroscopic imaging techniques impede the precise investigation of physiological parameters regulating this specialized lymphatic transport system. While NIR-II fluorescence imaging has demonstrated advantages in peripheral lymphatic imaging, there are few reports regarding its utilization in the glymphatic system. To address this, a noninvasive transcranial macroscopic NIR-II fluorescence imaging model is developed using a cyanine dye-protein coupled nanoprobe. NIR-II imaging with high temporal and spatial resolution reveals that hypothermia can increase the glymphatic influx by reducing the flow rate of cerebrospinal fluid. In addition, respiratory rate, respiratory amplitude, and heart rate all play a role in regulating the glymphatic influx. Thus, targeting the glymphatic influx may alter the trajectory of immune inflammation following brain injury, providing therapeutic prospects for treating brain injury with mild hypothermia.
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Lesiones Encefálicas , Sistema Glinfático , Animales , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/metabolismo , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/terapia , Ratones , Imagen Óptica , Hipotermia/metabolismo , Enfermedades Neuroinflamatorias/diagnóstico por imagen , Enfermedades Neuroinflamatorias/metabolismo , Rayos Infrarrojos , Colorantes Fluorescentes/química , Masculino , Hipotermia Inducida , Ratones Endogámicos C57BL , Carbocianinas/químicaRESUMEN
BACKGROUND: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. METHODS: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. RESULTS: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096â¯bp to -1087â¯bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. CONCLUSIONS: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.
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Astrocitos , Disfunción Cognitiva , Sistema Glinfático , Hipocampo , Ketamina , Animales , Ketamina/farmacología , Ketamina/toxicidad , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Ratones , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Acuaporina 4/metabolismo , Acuaporina 4/genética , Receptor de Serotonina 5-HT2C/metabolismo , Receptor de Serotonina 5-HT2C/genética , Ratones Endogámicos C57BL , Células Cultivadas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genéticaRESUMEN
BACKGROUND: Both glymphatic system dysfunction and inflammatory response aggravate neurological dysfunction after subarachnoid hemorrhage (SAH). Studies have shown that ß-hydroxybutyrate (BHB) may mitigate painful diabetic neuropathy (PDN) by upregulating SNTA1 expression and reinstating AQP4 polarity. However, the potential of BHB to ameliorate glymphatic system function and inflammatory response in SAH mice remains uncertain. METHODS: The SAH models were constructed by injection of arterial blood into cisterna Magana. Three groups of C57 mice were randomly assigned: Sham, SAH, and BHB. All mice were subjected to neurological function assessment, western blot, immunofluorescence double staining, and RNA-seq. Glymphatic system function was examined with tracer and immunofluorescence double staining, and the differential genes were examined with RNA-seq. In addition, the expression of related inflammation was detected. RESULTS: Compared with the SAH group, BHB reinstated AQP4 polarization by upregulating SNTA1 protein to enhance the glymphatic system. According to RNA-seq, the different genes were primarily connected to microglia activation, astrocytes, and inflammation. Western blot and immunofluorescence further confirmed that the related inflammatory protein expression levels were upregulated. BHB attenuated neuroinflammation after SAH. Ultimately, it can mitigate the neurological deficits in SAH mice. CONCLUSION: The study reveals a novel mechanism that BHB treatment mitigates neurologic impairment in SAH mice. We propose that BHB may play a neuroprotective effect by enhancing glymphatic system function and attenuating neuroinflammatory subarachnoid hemorrhage.
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Ácido 3-Hidroxibutírico , Sistema Glinfático , Ratones Endogámicos C57BL , Hemorragia Subaracnoidea , Animales , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/tratamiento farmacológico , Ratones , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Masculino , Ácido 3-Hidroxibutírico/farmacología , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/etiología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismoRESUMEN
The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.
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Péptidos beta-Amiloides , Encéfalo , Angiopatía Amiloide Cerebral , Humanos , Encéfalo/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Animales , Péptidos beta-Amiloides/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patologíaRESUMEN
Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28â days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.
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Acuaporina 4 , Traumatismos por Explosión , Sistema Glinfático , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Acuaporina 4/metabolismo , Traumatismos por Explosión/complicaciones , Traumatismos por Explosión/patología , Traumatismos por Explosión/metabolismo , Conmoción Encefálica/metabolismo , Conmoción Encefálica/complicaciones , Conmoción Encefálica/patología , Conmoción Encefálica/fisiopatología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Lóbulo Frontal/diagnóstico por imagen , Sistema Glinfático/metabolismo , Sistema Glinfático/patología , Imagen por Resonancia Magnética , Ratones Endogámicos C57BL , VeteranosRESUMEN
The glymphatic system is considered to play a pivotal role in the clearance of disease-causing proteins in neurodegenerative diseases. This study employed MR diffusion tensor imaging (DTI) to evaluate glymphatic system function and its correlation with brain amyloid accumulation levels measured using [11C]Pittsburgh compound-B (PiB) PET/MRI. Fifty-six patients with mild cognitive impairment and early Alzheimer's disease (AD: 70 ± 11 y) underwent [11C]PiB PET/MRI to assess amyloid deposition and were compared with 27 age-matched cognitively normal volunteers (CN: 69 ± 10y). All participants were evaluated for cognitive function using the Mini Mental State Examination (MMSE) before [11C]PiB PET/MRI. DTI images were acquired during the PET/MRI scan with several other MR sequences. The DTI analysis along the perivascular space index (DTI-ALPS index) was calculated to estimate the functional activity of the glymphatic system. Centiloid scale was applied to quantify amyloid deposition levels from [11C]PiB PET images. All patients in the AD group showed positive [11C]PiB accumulation, whereas all CN participants were negative. ALPS-index for all subjects linearly correlated with PiB centiloid, MMSE scores, and hippocampal volume. The correlation between the ALPS-index and PiB accumulation was more pronounced than with any other biomarkers. These findings suggest that glymphatic system dysfunction is a significant factor in the early stages of Alzheimer's disease.
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Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Sistema Glinfático , Imagen por Resonancia Magnética , Imagen Multimodal , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Anciano , Masculino , Femenino , Tomografía de Emisión de Positrones/métodos , Imagen por Resonancia Magnética/métodos , Biomarcadores/metabolismo , Imagen Multimodal/métodos , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/metabolismo , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Imagen de Difusión Tensora/métodos , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tiazoles , Compuestos de AnilinaRESUMEN
BACKGROUND: The aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer's and Parkinson's disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. METHODS: In this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. RESULTS: Our findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the alterations were attenuated. CONCLUSIONS: These results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.
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Enfermedad de Alzheimer , Sistema Glinfático , Niacinamida/análogos & derivados , Tiadiazoles , Ratones , Animales , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Proteínas tau/metabolismoRESUMEN
We hypothesized that early intra-central nervous system (CNS) responses in a murine model of decompression sickness (DCS) would be reflected by changes in the microparticles (MPs) that exit the brain via the glymphatic system, and due to systemic responses the MPs would cause inflammatory changes lasting for many days leading to functional neurological deficits. Elevations on the order of threefold of blood-borne inflammatory MPs, neutrophil activation, glymphatic flow, and neuroinflammation in cerebral cortex and hippocampus were found in mice at 12 days after exposure to 760 kPa of air for 2 h. Mice also exhibited a significant decline in memory and locomotor activity, as assessed by novel object recognition and rotarod testing. Similar inflammatory changes in blood, neuroinflammation, and functional impairments were initiated in naïve mice by injection of filamentous (F-) actin-positive MPs, but not F-actin-negative MPs, obtained from decompressed mice. We conclude that high pressure/decompression stress establishes a systemic inflammatory process that results in prolonged neuroinflammation and functional impairments in the mouse decompression model.NEW & NOTEWORTHY Elevated glymphatic flow due to astrocyte and microglial activation from high-pressure exposure triggers release of microparticles (MPs) to the circulation where neutrophil activation and production of filamentous (F)-actin expressing MPs result in a persistent feed-forward neuroinflammatory cycle and functional deficits lasting for at least 12 days.
Asunto(s)
Enfermedad de Descompresión , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Animales , Enfermedad de Descompresión/fisiopatología , Enfermedad de Descompresión/metabolismo , Ratones , Masculino , Enfermedades Neuroinflamatorias/fisiopatología , Enfermedades Neuroinflamatorias/metabolismo , Micropartículas Derivadas de Células/metabolismo , Sistema Glinfático/fisiopatología , Sistema Glinfático/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Hipocampo/metabolismo , Hipocampo/fisiopatología , Inflamación/fisiopatología , Inflamación/metabolismo , Activación NeutrófilaRESUMEN
BACKGROUND: Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aß and tau proteins. There has long been a keen interest among researchers in understanding how Aß and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD. Furthermore, there is a growing emphasis and discussion regarding the possibility that activating the glymphatic/meningeal lymphatic system could serve as a novel therapeutic strategy against AD. OBJECTIVES: Given this current research trend, the primary focus of this comprehensive review is to highlight the role of the glymphatic/meningeal lymphatic system in the pathogenesis of AD. The discussion will encompass future research directions and prospects for treatment in relation to the glymphatic/meningeal lymphatic system.