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Gut May 2019Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to...
OBJECTIVE
Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.
DESIGN
Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.
RESULTS
Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.
CONCLUSIONS
Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.
Topics: Adalimumab; Adolescent; Adult; Aged; Aged, 80 and over; Crohn Disease; Drug Resistance; Gastrointestinal Agents; Humans; Infliximab; Interleukin-17; Intestinal Mucosa; Male; Middle Aged; Receptors, Interleukin; Receptors, Tumor Necrosis Factor, Type II; T-Lymphocytes; Young Adult
PubMed: 29848778
DOI: 10.1136/gutjnl-2017-315671 -
Antioxidants (Basel, Switzerland) Nov 2022In this article we have reviewed the potential role of coenzyme Q10 (CoQ10) in the pathogenesis and treatment of a number of less common age-related disorders, for many... (Review)
Review
In this article we have reviewed the potential role of coenzyme Q10 (CoQ10) in the pathogenesis and treatment of a number of less common age-related disorders, for many of which effective therapies are not currently available. For most of these disorders, mitochondrial dysfunction, oxidative stress and inflammation have been implicated in the disease process, providing a rationale for the potential therapeutic use of CoQ10, because of its key roles in mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. Disorders reviewed in the article include multi system atrophy, progressive supranuclear palsy, sporadic adult onset ataxia, and pulmonary fibrosis, together with late onset versions of Huntington's disease, Alexander disease, lupus, anti-phospholipid syndrome, lysosomal storage disorders, fibromyalgia, Machado-Joseph disease, acyl-CoA dehydrogenase deficiency, and Leber's optic neuropathy.
PubMed: 36421479
DOI: 10.3390/antiox11112293 -
Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model.Brain : a Journal of Neurology Feb 2024Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of...
Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology. Functional changes in microglia were assessed by Ca2+ imaging using hippocampal brain slices from Iba1-GCaMP6-60TM mice and two-photon microscopy. We found that AxD microglia showed aberrant Ca2+ signals, with high frequency Ca2+ signals in both the processes and cell bodies. These microglial Ca2+ signals were inhibited by pharmacological blockade or genetic knockdown of P2Y12 receptors but not by tetrodotoxin, indicating that these signals are independent of neuronal activity but dependent on extracellular ATP from non-neuronal cells. Our single-cell RNA sequencing data showed that the expression level of Entpd2, an astrocyte-specific gene encoding the ATP-degrading enzyme NTPDase2, was lower in AxD astrocytes than in wild-type astrocytes. In situ ATP imaging using the adeno-associated virus vector GfaABC1D ATP1.0 showed that exogenously applied ATP was present longer in 60TM mice than in wild-type mice. Thus, the increased ATP level caused by the decrease in its metabolizing enzyme in astrocytes could be responsible for the enhancement of microglial Ca2+ signals. To determine whether these P2Y12 receptor-mediated Ca2+ signals in AxD microglia play a significant role in the pathological mechanism, a P2Y12 receptor antagonist, clopidogrel, was administered. Clopidogrel significantly exacerbated pathological markers in AxD model mice and attenuated the morphological features of microglia, suggesting that microglia play a protective role against AxD pathology via P2Y12 receptors. Taken together, we demonstrated that microglia sense AxD astrocyte dysfunction via P2Y12 receptors as an increase in extracellular ATP and alter their morphology and Ca2+ signalling, thereby protecting against AxD pathology. Although AxD is a primary astrocyte disease, our study may facilitate understanding of the role of microglia as a disease modifier, which may contribute to the clinical diversity of AxD.
Topics: Mice; Animals; Alexander Disease; Glial Fibrillary Acidic Protein; Astrocytes; Microglia; Clopidogrel; Calcium; Disease Progression; Adenosine Triphosphate
PubMed: 37955589
DOI: 10.1093/brain/awad358 -
Brain Pathology (Zurich, Switzerland) May 2018Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in... (Review)
Review
Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in the CNS do not express GFAP, AxD is a primary astrocyte disease. Astrocytes acquire a large number of pathological features, including changes in morphology, the loss or diminution of a number of critical astrocyte functions and the activation of cell stress and inflammatory pathways. AxD is also characterized by white matter degeneration, a pathology that has led it to be included in the "leukodystrophies." Furthermore, variable degrees of neuronal loss take place. Thus, the astrocyte pathology triggers alterations in other cell types. Here, we will review the neuropathology of AxD and discuss how a disease of astrocytes can lead to severe pathologies in non-astrocytic cells. Our knowledge of the pathophysiology of AxD will also lead to a better understanding of how astrocytes interact with other CNS cells and how astrocytes in the gliosis that accompanies many neurological disorders can damage the function and survival of other cells.
Topics: Alexander Disease; Animals; Astrocytes; Disease Models, Animal; Humans; Mice, Transgenic; Neurons; Oligodendroglia
PubMed: 29740945
DOI: 10.1111/bpa.12601 -
Pharmaceutics Nov 2022Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the... (Review)
Review
Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed.
PubMed: 36365206
DOI: 10.3390/pharmaceutics14112389 -
IUBMB Life Apr 2020Autophagy is a highly conserved cellular degradation process involving lysosomal degradation for the turnover of proteins, protein complexes, and organelles. Defects in... (Review)
Review
Autophagy is a highly conserved cellular degradation process involving lysosomal degradation for the turnover of proteins, protein complexes, and organelles. Defects in autophagy produces impaired intercellular communication and have subsequently been shown to be associated with pathological conditions, including neurodegenerative diseases. Curcumin is a polyphenol found in the rhizome of Curcuma longa, which has been shown to exert health benefits, such as antimicrobial, antioxidant, anti-inflammatory, and anticancer effects. There is increasing evidence in the literature revealing that autophagy modulation may provide neuroprotective effects. In light of this, our current review aims to address recent advances in the neuroprotective role of curcumin-induced autophagy modulation, specifically with a particular focus on its effects in Alexander disease, Alzheimer's disease, ischemia stroke, traumatic brain injury, and Parkinson's disease.
Topics: Autophagy; Biological Availability; Brain Injuries, Traumatic; Brain Neoplasms; Curcumin; Diabetes Mellitus; Humans; Neurodegenerative Diseases; Neuroprotective Agents
PubMed: 31804772
DOI: 10.1002/iub.2209 -
The Journal of Neuroscience : the... Mar 2022Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues...
Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using , rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia. Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or "rising from the dead." The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an important brain disorder in which glial cells promote neuronal dysfunction and death, anastasis of astrocytic glia leads to secretion of toxic signaling molecules and neurodegeneration. These studies demonstrate a previously unexpected deleterious consequence of rescuing cells on the brink of death and suggest therapeutic strategies for Alexander disease and related disorders of glia.
Topics: Alexander Disease; Animals; Apoptosis; Cell Death Reversal; Drosophila; Female; Humans; Male; Neuroglia; Neurons; Rats
PubMed: 35105675
DOI: 10.1523/JNEUROSCI.1659-21.2021 -
Experimental Cell Research Jun 2007Here we review how GFAP mutations cause Alexander disease. The current data suggest that a combination of events cause the disease. These include: (i) the accumulation... (Review)
Review
Here we review how GFAP mutations cause Alexander disease. The current data suggest that a combination of events cause the disease. These include: (i) the accumulation of GFAP and the formation of characteristic aggregates, called Rosenthal fibers, (ii) the sequestration of the protein chaperones alpha B-crystallin and HSP27 into Rosenthal fibers, and (iii) the activation of both Jnk and the stress response. These then set in motion events that lead to Alexander disease. We discuss parallels with other intermediate filament diseases and assess potential therapies as part of this review as well as emerging trends in disease diagnosis and other aspects concerning GFAP.
Topics: Alexander Disease; Animals; Astrocytes; Brain; Genetic Predisposition to Disease; Glial Fibrillary Acidic Protein; Humans; Inclusion Bodies; Intermediate Filaments; Molecular Chaperones; Mutation
PubMed: 17498694
DOI: 10.1016/j.yexcr.2007.04.004 -
Cureus May 2022Alexander disease is an uncommon autosomal dominant leukodystrophy that influences the white matter of the central nervous system (CNS), predominantly affecting the...
Alexander disease is an uncommon autosomal dominant leukodystrophy that influences the white matter of the central nervous system (CNS), predominantly affecting the frontal lobe bilaterally. The most obvious pathogenic hallmark is the extensive deposition of cytoplasmic inclusions known as "Rosenthal fibers" in perivascular, subpial, and subependymal astrocytes throughout the CNS. The hereditary cause is mutations in the glial fibrillary acidic protein (GFAP) gene. Infantile, adult, and juvenile onsets are the three subtypes. Psychomotor retardation, mile-stone regression, spastic paresis, brain stem symptoms (swallowing, speech, etc.), and seizures define the juvenile variety, which emerges between the ages of three and 10 years. Macrocephaly has a lower likelihood of being a juvenile type. It is generally diagnosed based on clinical and magnetic resonance imaging findings. A five-year-old girl is presented as a case of juvenile Alexander disease, with typical clinical and MRI features.
PubMed: 35698668
DOI: 10.7759/cureus.24870 -
Nature Communications May 2018Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial...
Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.
Topics: Adolescent; Adult; Alexander Disease; Animals; Behavior, Animal; Biomechanical Phenomena; Brain; Brain Chemistry; Child; Child, Preschool; Drosophila; Female; Glial Fibrillary Acidic Protein; Hippo Signaling Pathway; Humans; Infant; Lamin Type A; Male; Mechanotransduction, Cellular; Mice; Mice, Transgenic; Neuroglia; Protein Serine-Threonine Kinases; Young Adult
PubMed: 29765022
DOI: 10.1038/s41467-018-04269-7