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1.
Alzheimers Res Ther ; 16(1): 71, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38576025

RESUMO

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.


Assuntos
Doença de Alzheimer , Sistema Glinfático , Niacinamida/análogos & derivados , Tiadiazóis , Camundongos , Animais , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Proteínas tau/metabolismo
2.
Hum Brain Mapp ; 45(5): e26680, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38590180

RESUMO

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.


Assuntos
Sistema Glinfático , Esclerose Múltipla , Neuromielite Óptica , Humanos , Imagem de Tensor de Difusão/métodos , Esclerose Múltipla/diagnóstico por imagem , Neuromielite Óptica/diagnóstico por imagem , Teorema de Bayes , Sistema Glinfático/diagnóstico por imagem , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Água
3.
J R Soc Interface ; 21(213): 20230659, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38565158

RESUMO

The flow of cerebrospinal fluid (CSF) along perivascular spaces (PVSs) is an important part of the brain's system for clearing metabolic waste. Astrocyte endfeet bound the PVSs of penetrating arteries, separating them from brain extracellular space. Gaps between astrocyte endfeet might provide a low-resistance pathway for fluid transport across the wall. Recent studies suggest that the astrocyte endfeet function as valves that rectify the CSF flow, producing the net flow observed in pial PVSs by changing the size of the gaps in response to pressure changes. In this study, we quantify this rectification based on three features of the PVSs: the quasi-circular geometry, the deformable endfoot wall, and the pressure oscillation inside. We provide an analytical model, based on the thin-shell hoop-stress approximation, and predict a pumping efficiency of about 0.4, which would contribute significantly to the observed flow. When we add the flow resistance of the extracellular space (ECS) to the model, we find an increased net flow during sleep, due to the known increase in ECS porosity (decreased flow resistance) compared to that in the awake state. We corroborate our analytical model with three-dimensional fluid-solid interaction simulations.


Assuntos
Sistema Glinfático , Sistema Glinfático/fisiologia , Encéfalo/irrigação sanguínea , Artérias/fisiologia , Pressão , Transporte Biológico , Líquido Cefalorraquidiano/metabolismo
4.
Neuroreport ; 35(7): 476-485, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38597326

RESUMO

The objective of this study is to explore the relationship between the glymphatic system and alterations in the structure and function of the brain in white matter hyperintensity (WMH) patients. MRI data were collected from 27 WMH patients and 23 healthy controls. We calculated the along perivascular space (ALPS) indices, the anterior corner distance of the lateral ventricle, and the width of the third ventricle for each subject. The DPABISurf tool was used to calculate the cortical thickness and cortical area. In addition, data processing assistant for resting-state fMRI was used to calculate regional homogeneity, degree centrality, amplitude low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), and voxel-mirrored homotopic connectivity (VMHC). In addition, each WMH patient was evaluated on the Fazekas scale. Finally, the correlation analysis of structural indicators and functional indicators with bilateral ALPS indices was investigated using Spearman correlation analysis. The ALPS indices of WMH patients were lower than those of healthy controls (left: t = -4.949, P < 0.001; right: t = -3.840, P < 0.001). This study found that ALFF, fALFF, regional homogeneity, degree centrality, and VMHC values in some brain regions of WMH patients were alternated (AlphaSim corrected, P < 0.005, cluster size > 26 voxel, rmm value = 5), and the cortical thickness and cortical area of WMH patients showed trend changes (P < 0.01, cluster size > 20 mm2, uncorrected). Interestingly, we found significantly positive correlations between the left ALPS indices and degree centrality values in the superior temporal gyrus (r = 0.494, P = 0.009, P × 5 < 0.05, Bonferroni correction). Our results suggest that glymphatic system impairment is related to the functional centrality of local connections in patients with WMH. This provides a new perspective for understanding the pathological mechanisms of cognitive impairment in the WMH population.


Assuntos
Sistema Glinfático , Substância Branca , Humanos , Sistema Glinfático/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Imageamento por Ressonância Magnética/métodos
5.
Fluids Barriers CNS ; 21(1): 28, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38532513

RESUMO

Waste from the brain has been shown to be cleared via the perivascular spaces through the so-called glymphatic system. According to this model the cerebrospinal fluid (CSF) enters the brain in perivascular spaces of arteries, crosses the astrocyte endfoot layer, flows through the parenchyma collecting waste that is subsequently drained along veins. Glymphatic clearance is dependent on astrocytic aquaporin-4 (AQP4) water channels that are highly enriched in the endfeet. Even though the polarized expression of AQP4 in endfeet is thought to be of crucial importance for glymphatic CSF influx, its role in extracellular solute clearance has only been evaluated using non-quantitative fluorescence measurements. Here we have quantitatively evaluated clearance of intrastriatally infused small and large radioactively labeled solutes in mice lacking AQP4 (Aqp4-/-) or lacking the endfoot pool of AQP4 (Snta1-/-). We confirm that Aqp4-/- mice show reduced clearance of both small and large extracellular solutes. Moreover, we find that the Snta1-/- mice have reduced clearance only for the 500 kDa [3H]dextran, but not 0.18 kDa [3H]mannitol suggesting that polarization of AQP4 to the endfeet is primarily important for clearance of large, but not small molecules. Lastly, we observed that clearance of 500 kDa [3H]dextran increased with age in adult mice. Based on our quantitative measurements, we confirm that presence of AQP4 is important for clearance of extracellular solutes, while the perivascular AQP4 localization seems to have a greater impact on clearance of large versus small molecules.


MAIN POINTS: Solute clearance is reduced in mice lacking AQP4 Polarization of AQP4 to the endfeet may have a greater impact on clearance of large versus small molecules Clearance of large but not small solutes is correlated with age within adult age.


Assuntos
Dextranos , Sistema Glinfático , Animais , Camundongos , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Dextranos/metabolismo , Sistema Glinfático/metabolismo
6.
Methods Mol Biol ; 2754: 343-349, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512675

RESUMO

Despite being a cytoplasmic protein abundant in neurons, tau is detectable in various extracellular fluids. In addition to being passively released from dying/degenerating neurons, tau is also actively released from living neurons in a neuronal activity-dependent mechanism. In vivo, tau released from neurons first appears in brain interstitial fluid (ISF) and subsequently drains into cerebrospinal fluid (CSF) by glymphatic system. Changes in CSF tau levels alter during the course of AD pathogenesis and are considered to predict the disease-progression of AD. A method to collect CSF from various mouse models of AD will serve as a valuable tool to investigate the dynamics of physiological/pathological tau released from neurons. In this chapter, we describe and characterize a method that reliably collects a relatively large volume of CSF from anesthetized mice.


Assuntos
Doença de Alzheimer , Sistema Glinfático , Camundongos , Animais , Proteínas tau/metabolismo , Cisterna Magna/metabolismo , Encéfalo/metabolismo , Líquido Extracelular/metabolismo , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Peptídeos beta-Amiloides/metabolismo
7.
Methods Mol Biol ; 2754: 351-359, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512676

RESUMO

Glymphatic system denotes a brain-wide pathway that eliminates extracellular solutes from brain. It is driven by the flow of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) via perivascular spaces. Glymphatic convective flow is driven by cerebral arterial pulsation, which is facilitated by a water channel, aquaporin-4 (AQP4) expressed in astrocytic end-foot processes. Since its discovery, the glymphatic system receives a considerable scientific attention due to its pivotal role in clearing metabolic waste as well as neurotoxic substances such as amyloid b peptide. Tau is a microtubule binding protein, however it is also physiologically released into extracellular fluids. The presence of tau in the blood stream indicates that it is eventually cleared from the brain to the periphery, however, the detailed mechanisms that eliminate extracellular tau from the central nervous system remained to be elucidated. Recently, we and others have reported that extracellular tau is eliminated from the brain to CSF by an AQP4 dependent mechanism, suggesting the involvement of the glymphatic system. In this chapter, we describe the detailed protocol of how we can assess glymphatic outflow of tau protein from brain to CSF in mice.


Assuntos
Sistema Glinfático , Proteínas tau , Camundongos , Animais , Proteínas tau/metabolismo , Encéfalo/metabolismo , Líquido Extracelular/metabolismo , Aquaporina 4/metabolismo , Líquido Cefalorraquidiano/metabolismo
8.
Neuropharmacology ; 250: 109907, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38492884

RESUMO

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. ß-Dystroglycan (ß-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated ß-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, ß-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased ß-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Ginkgolídeos , Sistema Glinfático , Lactonas , Ratos , Animais , Sistema Glinfático/metabolismo , Metaloproteinase 9 da Matriz , Neuroproteção , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Medula Espinal/metabolismo , Aquaporina 4/metabolismo
9.
CNS Neurosci Ther ; 30(3): e14669, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38459666

RESUMO

BACKGROUND: Diffuse brain injury (DBI) models are characterized by intense global brain inflammation and edema, which characterize the most severe form of TBI. In a previous experiment, we found that fingolimod promoted recovery after controlled cortical impact injury (CCI) by modulating inflammation around brain lesions. However, it remains unclear whether fingolimod can also attenuate DBI because of its different injury mechanisms. Furthermore, whether fingolimod has additional underlying effects on repairing DBI is unknown. METHODS: The impact acceleration model of DBI was established in adult Sprague-Dawley rats. Fingolimod (0.5 mg/kg) was administered 0.5, 24, and 48 h after injury for 3 consecutive days. Immunohistochemistry, immunofluorescence analysis, cytokine array, and western blotting were used to evaluate inflammatory cells, inflammatory factors, AQP4 polarization, apoptosis in brain cells, and the accumulation of APP after DBI in rats. To evaluate the function of the glymphatic system (GS), a fluorescent tracer was injected into the cistern. The neural function of rats with DBI was evaluated using various tests, including the modified neurological severity score (mNSS), horizontal ladder-crossing test, beam walking test, and tape sensing and removal test. Brain water content was also measured. RESULTS: Fingolimod administration for 3 consecutive days could reduce the levels of inflammatory cytokines, neutrophil recruitment, microglia, and astrocyte activation in the brain following DBI. Moreover, fingolimod reduced apoptotic protein expression, brain cell apoptosis, brain edema, and APP accumulation. Additionally, fingolimod inhibited the loss of AQP4 polarization, improved lymphatic system function, and reduced damage to nervous system function. Notably, inhibiting the GS weakened the therapeutic effect of fingolimod on the neurological function of rats with DBI and increased the accumulation of APP in the brain. CONCLUSIONS: In brief, these findings suggest that fingolimod alleviates whole-brain inflammation and GS system damage after DBI and that inhibiting the GS could weaken the positive effect of fingolimod on nerve function in rats with DBI. Thus, inhibiting inflammation and regulating the GS may be critical for the therapeutic effect of fingolimod on DBI.


Assuntos
Edema Encefálico , Lesões Encefálicas Difusas , Lesões Encefálicas Traumáticas , Encefalite , Sistema Glinfático , Ratos , Animais , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Ratos Sprague-Dawley , Sistema Glinfático/metabolismo , Edema Encefálico/etiologia , Encefalite/complicações , Citocinas/metabolismo , Inflamação/complicações , Modelos Animais de Doenças , Lesões Encefálicas Traumáticas/patologia
10.
J Headache Pain ; 25(1): 34, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38462633

RESUMO

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.


Assuntos
Sistema Glinfático , Transtornos de Enxaqueca , Doenças do Sistema Nervoso , Animais , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/metabolismo , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/metabolismo , Barreira Hematoencefálica/metabolismo , Doenças do Sistema Nervoso/metabolismo , Cefaleia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo
11.
Nature ; 627(8002): 149-156, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38418876

RESUMO

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.


Assuntos
Doença de Alzheimer , Amiloide , Encéfalo , Líquido Cefalorraquidiano , Líquido Extracelular , Ritmo Gama , Sistema Glinfático , Animais , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Amiloide/metabolismo , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Líquido Cefalorraquidiano/metabolismo , Modelos Animais de Doenças , Líquido Extracelular/metabolismo , Sistema Glinfático/fisiologia , Interneurônios/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estimulação Elétrica
12.
Nature ; 627(8002): 157-164, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38418877

RESUMO

The accumulation of metabolic waste is a leading cause of numerous neurological disorders, yet we still have only limited knowledge of how the brain performs self-cleansing. Here we demonstrate that neural networks synchronize individual action potentials to create large-amplitude, rhythmic and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow1,2 through the brain parenchyma. Chemogenetic flattening of these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial optogenetic stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. Our study demonstrates that neurons serve as master organizers for brain clearance. This fundamental principle introduces a new theoretical framework for the functioning of macroscopic brain waves.


Assuntos
Encéfalo , Líquido Cefalorraquidiano , Líquido Extracelular , Neurônios , Potenciais de Ação , Encéfalo/citologia , Encéfalo/metabolismo , Ondas Encefálicas/fisiologia , Líquido Cefalorraquidiano/metabolismo , Líquido Extracelular/metabolismo , Sistema Glinfático/metabolismo , Cinética , Rede Nervosa/fisiologia , Neurônios/metabolismo , Optogenética , Tecido Parenquimatoso/metabolismo , Íons/metabolismo
13.
Neurobiol Dis ; 192: 106426, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38331353

RESUMO

The term "glymphatic" emerged roughly a decade ago, marking a pivotal point in neuroscience research. The glymphatic system, a glial-dependent perivascular network distributed throughout the brain, has since become a focal point of investigation. There is increasing evidence suggesting that impairment of the glymphatic system appears to be a common feature of neurodegenerative disorders, and this impairment exacerbates as disease progression. Nevertheless, the common factors contributing to glymphatic system dysfunction across most neurodegenerative disorders remain unclear. Inflammation, however, is suspected to play a pivotal role. Dysfunction of the glymphatic system can lead to a significant accumulation of protein and waste products, which can trigger inflammation. The interaction between the glymphatic system and inflammation appears to be cyclical and potentially synergistic. Yet, current research is limited, and there is a lack of comprehensive models explaining this association. In this perspective review, we propose a novel model suggesting that inflammation, impaired glymphatic function, and neurodegenerative disorders interconnected in a vicious cycle. By presenting experimental evidence from the existing literature, we aim to demonstrate that: (1) inflammation aggravates glymphatic system dysfunction, (2) the impaired glymphatic system exacerbated neurodegenerative disorders progression, (3) neurodegenerative disorders progression promotes inflammation. Finally, the implication of proposed model is discussed.


Assuntos
Sistema Glinfático , Doenças Neurodegenerativas , Humanos , Encéfalo/metabolismo , Doenças Neurodegenerativas/metabolismo , Aquaporina 4 , Inflamação/metabolismo
14.
Glia ; 72(5): 982-998, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38363040

RESUMO

The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.


Assuntos
Clorofenóis , Sistema Glinfático , Camundongos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Clorofenóis/metabolismo , Aquaporina 4/genética , Aquaporina 4/metabolismo
15.
Curr Opin Neurol ; 37(2): 182-188, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38345416

RESUMO

PURPOSE OF REVIEW: Purpose of this review is to update the ongoing work in the field of glymphatic and neurodegenerative research and to highlight focus areas that are particularly promising. RECENT FINDINGS: Multiple reports have over the past decade documented that glymphatic fluid transport is broadly suppressed in neurodegenerative diseases. Most studies have focused on Alzheimer's disease using a variety of preclinical disease models, whereas the clinical work is based on various neuroimaging approaches. It has consistently been reported that brain fluid transport is impaired in patients suffering from Alzheimer's disease compared with age-matched control subjects. SUMMARY: An open question in the field is to define the mechanistic underpinning of why glymphatic function is suppressed. Other questions include the opportunities for using glymphatic imaging for diagnostic purposes and in treatment intended to prevent or slow Alzheimer disease progression.


Assuntos
Doença de Alzheimer , Sistema Glinfático , Doenças Neurodegenerativas , Humanos , Sistema Glinfático/diagnóstico por imagem , Doença de Alzheimer/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem
16.
Sleep Med ; 115: 145-151, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38364456

RESUMO

BACKGROUND: Chronic insomnia impairs the glymphatic system and may lead to cognitive impairment and dementia in elderly population. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed as a non-invasive method to measure the activity of human brain glymphatic. We aim to explore whether glymphatic function is impaired in middle-aged and elderly chronic insomnia individuals and to identify the relationships between glymphatic dysfunction and cognitive impairment. METHODS: A total of 33 chronic insomnia patients (57.36 ± 5.44 years, 30 females) and 20 age- and sex-matched healthy controls (57.95 ± 5.78 years, 16 females) were prospectively enrolled between May 2022 and January 2023. All participants completed MRI screening, cognition and sleep assessments, and DTI-ALPS index analysis. RESULTS: Our findings revealed that the DTI-ALPS index was significantly difference among the chronic insomnia patients with impaired cognition group (1.32 ± 0.14), with normal cognition group (1.46 ± 0.09), and healthy controls (1.61 ± 0.16) (p = 0.0012, p < 0.0001, p = 0.0008, respectively). Mini-Mental State Examination (MMSE) scores of chronic insomnia patients with cognitive impairment were positively correlated with the DTI-ALPS index (Partial correlation analyses after correction for age, sex, education level and duration of chronic insomnia: r = 0.78, p = 0.002). DTI-ALPS had moderate accuracy in distinguishing chronic insomnia patients with cognitive impairment from those with normal cognition. DATA CONCLUSION: The glymphatic system dysfunction is involved in chronic insomnia among middle-aged and elderly individuals, and it has been found to be correlated with cognitive decline.


Assuntos
Disfunção Cognitiva , Sistema Glinfático , Distúrbios do Início e da Manutenção do Sono , Feminino , Pessoa de Meia-Idade , Humanos , Idoso , Sistema Glinfático/diagnóstico por imagem , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Imagem de Tensor de Difusão , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Cognição
17.
J Neurol Sci ; 458: 122900, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38310733

RESUMO

Interest in the health consequences of climate change (global warming, heatwaves) has increased in the neurological community. This review addresses the impact of elevated ambient temperatures and heatwaves on patients with neurological and mental health disorders, including multiple sclerosis, synucleinopathies, dementia, epilepsies, mental health, and stroke. Patients with such conditions are highly vulnerable during heatwaves because of functional disorders affecting sleep, thermoregulation, autonomic system reactivity, mood, and cognitive ability. Several medications may also increase the risk of heatstroke. Special attention is devoted to the involvement of common underlying mechanisms, such as sleep and the glymphatic system. Disease prevention and patient care during heatwaves are major issues for caregivers. Beyond the usual recommendations for individuals, we favor artificially induced acclimation to heat, which provides preventive benefits with proven efficacy for healthy adults.


Assuntos
Mudança Climática , Sistema Glinfático , Humanos , Regulação da Temperatura Corporal/fisiologia , Sono
18.
Cells ; 13(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38334678

RESUMO

The key to the effective treatment of neurodegenerative disorders is a thorough understanding of their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment of glymphatic system function in neurodegeneration contributes to the progression of pathological processes. The question arises as to how neuroinflammation and the glymphatic system are related. This review highlights the direct and indirect influence of these two seemingly independent processes. Protein aggregates, a characteristic feature of neurodegeneration, are correlated with glymphatic clearance and neuroinflammation. Glial cells cannot be overlooked when considering the neuroinflammatory processes. Astrocytes are essential for the effective functioning of the glymphatic system and play a crucial role in the inflammatory responses in the central nervous system. It is imperative to acknowledge the significance of AQP4, a protein that exhibits a high degree of polarization in astrocytes and is crucial for the functioning of the glymphatic system. AQP4 influences inflammatory processes that have not yet been clearly delineated. Another interesting issue is the gut-brain axis and microbiome, which potentially impact the discussed processes. A discussion of the correlation between the functioning of the glymphatic system and neuroinflammation may contribute to exploring the pathomechanism of neurodegeneration.


Assuntos
Sistema Glinfático , Humanos , Sistema Glinfático/metabolismo , Doenças Neuroinflamatórias , Encéfalo/metabolismo , Astrócitos/metabolismo , Fatores de Risco
19.
CNS Neurosci Ther ; 30(2): e14587, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38421142

RESUMO

INTRODUCTION: Neonatal stress disrupts brain development and increases the risk of neurological disorders later in life. However, the impact of neonatal stress on the development of the glymphatic system and susceptibility to Parkinson's disease (PD) remains largely unknown. METHODS: Neonatal maternal deprivation (NMD) was performed on mice for 14 consecutive days to model chronic neonatal stress. Adeno-associated virus expressing A53T-α-synuclein (α-syn) was injected into the substantia nigra to establish PD model mice. Glymphatic activity was determined using in vivo magnetic resonance imaging, ex vivo fluorescence imaging and microplate assay. The transcription and expression of aquaporin-4 (AQP4) and other molecules were evaluated by qPCR, western blotting, and immunofluorescence. Animal's responses to NMD and α-syn overexpression were observed using behavioral tests. RESULTS: Glymphatic activity was impaired in adult NMD mice. AQP4 polarization and platelet-derived growth factor B (PDGF-B) signaling were reduced in the frontal cortex and hippocampus of both young and adult NMD mice. Furthermore, exogenous α-syn accumulation was increased and PD-like symptoms were aggravated in adult NMD mice. CONCLUSION: The results demonstrated that NMD could disrupt the development of the glymphatic system through PDGF-B signaling and increase the risk of PD later in life, indicating that alleviating neonatal stress could be beneficial in protecting the glymphatic system and reducing susceptibility to neurodegeneration.


Assuntos
Sistema Glinfático , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/metabolismo , Sistema Glinfático/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Substância Negra , Modelos Animais de Doenças
20.
Brain Nerve ; 76(2): 117-122, 2024 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-38351557

RESUMO

The inflow channel of the glymphatic pathway is the basilar membrane formed by the pia matter and glial border membrane in the outermost layer of the artery. Cerebrospinal fluid from the subarachnoid space enters the brain parenchyma through this pathway, and its water component is pumped into the brain parenchyma through aquaporin 4. One of the driving forces is vascular pulsation, and if this pathway becomes inoperative, cerebrospinal fluid loses its normal dynamics and contributes to idiopathic normal pressure hydrocephalus. Future research is needed to determine the extent of this contribution to the development of idiopathic normal pressure hydrocephalus.


Assuntos
Sistema Glinfático , Hidrocefalia de Pressão Normal , Hidrocefalia , Humanos , Sistema Glinfático/metabolismo , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Encéfalo , Neuroglia , Aquaporina 4 , Hidrocefalia/metabolismo , Líquido Cefalorraquidiano/metabolismo
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