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Background. To assess whether Aquaporin-4 (AQP4) expression in skeletal muscle is altered in idiopathic inflammatory myopathies (IIMs), particularly in dysphagic patients, and to explore its association with muscle fiber type, regeneration, inflammation, and tissue damage.   Methods. Muscle biopsies from 54 IIM patients (25 dysphagic: 11 DM, 7 PM, 2 IBM, 2 IMNM, 3 OM; 29 normophagic: 9 DM, 4 ASyS, 4 PM, 4 IBM, 8 IMNM) and 6 non-inflammatory controls were analyzed using immunofluorescence and confocal microscopy. AQP4 immunolocalization was assessed alongside markers of fiber type (MHCfast), regeneration (neonatal myosin), inflammation (CD68), and matrix remodeling (MMP2). Morphometric parameters (fiber diameter, area, atrophy factor, variability coefficient) were quantified. Clinical correlations were examined using MMT-8 and the Myositis Damage Index (MDI).   Results. A significant reduction in AQP4-positive myofibers was observed in dysphagic IIM patients compared to normophagic patients and controls, predominantly affecting type 2 fibers. Dysphagic muscles showed marked hypotrophy, with reduced fiber diameter and area, and increased variability and atrophy indices. These changes were mainly driven by AQP4-negative type 2 fibers (Figure 1A-B). Dysphagic patients showed a significantly higher percentage of AQP4-negative fibers co-expressing neonatal myosin (p<0.001 vs normophagic IIMs and healthy controls), indicating impaired regeneration. AQP4-negative fibers were more frequently surrounded by CD68-positive macrophages and MMP2-positive vessels (p<0.001 vs healthy controls). The proximity of inflammatory and vascular cells to AQP4-negative sarcolemmas suggests inflammation-induced AQP4 loss. Anti-HMGCR-positive IMNM cases (red circles and triangles in Figure 1A) exhibited the most severe AQP4 reduction and fiber damage. In the overall IIM cohort, the percentage of AQP4-positive type 1 myofibers correlated positively with MMT-8 scores (r:0.383, p<0.01), while AQP4-negative type 1 and type 2 fibers correlated inversely (r:-0.389, p<0.01; r:-0.288, p<0.05, respectively). No significant correlation emerged with CK levels. MDI was negatively correlated with AQP4-positive type 1 (r:-0.433, p<0.01) and type 2 (r:–0.265, p=0.05) fibers, and positively correlated with AQP4-negative type 1 (r:0.442, p<0.01) and type 2 (r:0.265, p=0.05) fibers.   Conclusions. AQP4 loss in type 2 myofibers is a distinctive feature of dysphagic IIM patients and reflects myofiber damage, inflammation, and regenerative failure. AQP4 downregulation may represent a novel histopathological marker of disease severity and tissue vulnerability in IIMs.

This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings.

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

The term ‘neuromyelitis optica spectrum disorders’ (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options.

Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release.

Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD. The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aβ and abnormal tau clearance and is a potential therapeutic target for AD. However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood. Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies. The Branes maze task was conducted to measure spatial learning and memory. Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage. Sholl analysis was carried out to analyze the morphology of microglia. Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aβ, respectively. An APP/PS1 transgenic AD mice model was used to confirm the key findings. High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss. Additionally, HIIT improved the drainage of abnormal tau and Aβ from the cortex and hippocampus via the glymphatic system to the kidney. Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype. Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype. We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization. These changes promote Aβ and p-tau clearance from the brain tissue through the glymphatic system and the kidney.

Background Slowed clearance of amyloid β (Aβ) is believed to underlie the development of Aβ plaques that characterize Alzheimer’s disease (AD). Aβ is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aβ clearance, and promotes Aβ plaque formation. Methods To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin ( Snta1 ) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid β levels. Results In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aβ and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid β levels. Conclusions These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.

Aquaporin‐4 (AQP4), the main water‐selective membrane transport protein in the brain, is localized to the astrocyte plasma membrane. Following the establishment of a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson's disease (PD) model, AQP4‐deficient (AQP4−/−) mice displayed significantly stronger microglial inflammatory responses and remarkably greater losses of tyrosine hydroxylase (TH+)‐positive neurons than did wild‐type AQP4 (AQP4+/+) controls. Microglia are the most important immune cells that mediate immune inflammation in PD. However, recently, few studies have reported why AQP4 deficiency results in more severe hypermicrogliosis and neuronal damage after MPTP treatment. In this study, transforming growth factor‐β1 (TGF‐β1), a key suppressive cytokine in PD onset and development, failed to increase in the midbrain and peripheral blood of AQP4−/− mice after MPTP treatment. Furthermore, the lower level of TGF‐β1 in AQP4−/− mice partially resulted from impairment of its generation by astrocytes; reduced TGF‐β1 may partially contribute to the uncontrolled microglial inflammatory responses and subsequent severe loss of TH+ neurons in AQP4−/− mice after MPTP treatment. Our study provides not only a better understanding of both aetiological and pathogenical factors implicated in the neurodegenerative mechanism of PD but also a possible approach to developing new treatments for PD via intervention in AQP4‐mediated immune regulation.

The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid β that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain’s interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had 36% higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs.

Background Neuromyelitis optica spectrum disorders (NMOSD) are an immune‐mediated inflammatory disease of the central nervous system (CNS) primarily characterized by anti‐aquaporin‐4 immunoglobulin G (AQP4‐IgG)‐mediated astrocyte injury, neuroinflammation, and demyelination. However, the relationship between the disease and the immune trait from a genetic perspective still requires further confirmation. Methods This study used two‐sample Mendelian randomization (MR) to assess causal relationship of immune cells with NMOSD. A total of 731 immune phenotyping traits were considered as exposure factors. NMOSD group is defined as outcome factor, which single‐nucleotide polymorphisms (SNPs) obtained from the study of Karol Estrada et al. (n = 215 NMOSD cases). The disease group was subcategorized into three groups based on the presence of AQP4‐IgG or not. We then enrolled 27 NMOSD patients and 17 healthy controls for peripheral blood flow cytometric analyses to validate part of our findings. Results In this study, we found multiple possible genetic associations between immune cells and NMOSD. Beyond the well‐recognized roles of T and B cells, diverse myeloid‐lineage cells may also contribute to NMOSD pathophysiology. For AQP4‐IgG seropositive patient, myeloid cells, including dendritic cells (DCs) and the surface molecule CD80, granulocytic myeloid‐derived suppressor cells (MDSCs), and the molecule CX3CR1 may have a protective role in this group. In AQP4‐IgG seronegative patients, molecules like herpesvirus entry mediator (HVEM) exert pathogenic roles in NMOSD. Further flow‐cytometric analysis revealed that the proportion of MDSCs in NMOSD patients was lower, consistent with the MR analysis. However, the phenotypic expression of CX3CR1 in our NMOSD cohort yielded results opposite to those of the MR analysis. Additionally, many immune traits were correlated with the clinical phenotypes of NMOSD patients. Conclusio Adaptive immune cells play significant role in NMOSD patients.Certain innate immune cells (e.g., DCs and MDSCs) and surface molecules (e.g., CX3CR1 and CD80) may correlate with certain clinical phenotypes. This study used two‐sample Mendelian randomization to assess causal relationship of immune cells with NMOSD. We then enrolled 27 NMOSD patients and 17 healthy controls for peripheral blood flow cytometric analyses to validate part of MR findings.