Publications by authors named "Mingqin Zhu"

31 Publications

Case Report: Innate Immune System Challenge Unleashes Paraneoplastic Neurological Autoimmunity.

Front Neurol 2020 10;11:598894. Epub 2020 Dec 10.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.

Paraneoplastic autoimmune neurological disorders reflect tumor-initiated immune responses against onconeural antigens. Symptoms and signs can affect the central and/or peripheral nervous systems, neuromuscular junction or muscle, and typically evolve subacutely before an underlying neoplasm is discovered. We describe four patients whose neurological symptoms were precipitated by potent innate immune system challenges: bladder instillation of BCG, tick bite and an "alternative cancer therapy" with bacterial extracts and TNF-α. We hypothesize that a tumor-initiated autoimmune response (evidenced by autoantibody profiles), pre-dating the immune system challenge, was unmasked or amplified in these patients by cytokines released systemically from innate immune cells activated by microbial pathogen-associated molecular patterns (PAMPs). The resultant upregulation of cognate onconeural peptides as MHC1 protein complexes on neural cell surfaces would render those cells susceptible to killing by CD8+ T cells, thus precipitating the patient's neurological symptoms.
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http://dx.doi.org/10.3389/fneur.2020.598894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759151PMC
December 2020

Mechanical ventilation in Guillain-Barré syndrome.

Expert Rev Clin Immunol 2020 11 25;16(11):1053-1064. Epub 2020 Nov 25.

Department of Life Sciences, National Natural Science Foundation of China , Beijing, China.

: Up to 30% of patients with GuillainBarré syndrome (GBS) develop respiratory failure requiring intensive care unit (ICU) admission and mechanical ventilation. Progressive weakness of the respiratory muscles is the leading cause of acute respiratory distress and respiratory failure with hypoxia and/or hypercarbia. Bulbar weakness may compromise airway patency and predispose patients to aspiration pneumonia. : Clinical questions related to the use of mechanical ventilation include but are not limited to: When to start? Invasive or noninvasive? When to wean from mechanical ventilation? When to perform tracheostomy? How to manage complications of GBS in the ICU including nosocomial infection, ventilator-associated pneumonia, and ICU-acquired weakness? In this narrative review, the authors summarize the up-to-date knowledge of the incidence, pathophysiology, evaluation, and general management of respiratory failure in GBS. : Respiratory failure in GBS merits more attention from caregivers. Emergency intubation may lead to life-threatening complications. Appropriate methods and time point of intubation and weaning, an early tracheostomy, and predictive prophylaxis of complications benefit patients' long-term prognosis.
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http://dx.doi.org/10.1080/1744666X.2021.1840355DOI Listing
November 2020

Progressive Encephalomyelitis With Rigidity and Myoclonus With Thymoma: A Case Report and Literature Review.

Front Neurol 2020 18;11:1017. Epub 2020 Sep 18.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is part of the variant type of the Stiff Person Syndrome (SPS) and is a rare neurological disease. We report here a patient with PERM who had thymoma and was positive for anti-glutamic acid decarboxylase (anti-GAD) antibodies. Her symptoms improved after treatment with hormones and gamma globulin. We also summarized the literature review of patients with PERM accompanied by tumors reported.
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http://dx.doi.org/10.3389/fneur.2020.01017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533529PMC
September 2020

Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment.

Mol Neurobiol 2020 Dec 23;57(12):5026-5043. Epub 2020 Aug 23.

Department of Life Sciences, National Natural Science Foundation of China, Shuangqing Road 83, Beijing, 100085, China.

Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term "microbiota-gut-brain axis" from "gut-brain axis" underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer's disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.
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http://dx.doi.org/10.1007/s12035-020-02073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541367PMC
December 2020

Double seropositivity for AChR and MuSK autoantibodies in myasthenia gravis.

Neuromuscul Disord 2020 07 19;30(7):533. Epub 2020 May 19.

Neuroimmunology Laboratory, Mayo Clinic Rochester MN, USA. Electronic address:

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http://dx.doi.org/10.1016/j.nmd.2020.04.003DOI Listing
July 2020

Axonal variants of Guillain-Barré syndrome: an update.

J Neurol 2020 Mar 5. Epub 2020 Mar 5.

Department of Life Sciences, National Natural Science Foundation of China, Shuangqing Road 83#, Beijing, 100085, China.

Axonal variants of Guillain-Barré syndrome (GBS) mainly include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and pharyngeal-cervical-brachial weakness. Molecular mimicry of human gangliosides by a pathogen's lipooligosaccharides is a well-established mechanism for Campylobacter jejuni-associated GBS. New triggers of the axonal variants of GBS (axonal GBS), such as Zika virus, hepatitis viruses, intravenous administration of ganglioside, vaccination, and surgery, are being identified. However, the pathogenetic mechanisms of axonal GBS related to antecedent bacterial or viral infections other than Campylobacter jejuni remain unknown. Currently, autoantibody classification and serial electrophysiology are cardinal approaches to differentiate axonal GBS from the prototype of GBS, acute inflammatory demyelinating polyneuropathy. Newly developed technologies, including metabolite analysis, peripheral nerve ultrasound, and feature selection via artificial intelligence are facilitating more accurate diagnosis of axonal GBS. Nevertheless, some key issues, such as genetic susceptibilities, remain unanswered and moreover, current therapies bear limitations. Although several therapies have shown considerable benefits to experimental animals, randomized controlled trials are still needed to validate their efficacy.
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http://dx.doi.org/10.1007/s00415-020-09742-2DOI Listing
March 2020

Maresin1 Decreased Microglial Chemotaxis and Ameliorated Inflammation Induced by Amyloid-β42 in Neuron-Microglia Co-Culture Models.

J Alzheimers Dis 2020 ;73(2):503-515

Department of Neurology, The First Hospital of Jilin University, Changchun, China.

Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer's disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42. The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42, and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition.
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http://dx.doi.org/10.3233/JAD-190682DOI Listing
November 2020

Inflammation resolution and specialized pro-resolving lipid mediators in CNS diseases.

Expert Opin Ther Targets 2019 11 20;23(11):967-986. Epub 2019 Nov 20.

Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China.

: Inflammation resolution induced by specialized pro-resolving lipid mediators (SPMs) is a new concept. The application of SPMs is a promising therapeutic strategy that can potentially supersede anti-inflammatory drugs. Most CNS diseases are associated with hyperreactive inflammatory damage. CNS inflammation causes irreversible neuronal loss and permanent functional impairments. Given the high mortality and morbidity rates, the investigation of therapeutic strategies to ameliorate inflammatory damage is necessary.: In this review, we explore inflammation resolution in CNS disorders. We discuss the underlying mechanisms and dynamic changes of SPMs and their precursors in neurological diseases and examine how this can potentially be incorporated into the clinic. References were selected from PubMed; most were published between 2010 and 2019.: Inflammation resolution is a natural process that emerges after acute or chronic inflammation. The evidence that SPMs can effectively ameliorate hyperreactive inflammation, shorten resolution time and accelerate tissue regeneration in CNS disorders. Adjuvants and nanotechnology offer opportunities for SPM drug design; however, more preclinical studies are necessary to investigate basic, critical issues such as safety.
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http://dx.doi.org/10.1080/14728222.2019.1691525DOI Listing
November 2019

Maresin 1 Improves Cognitive Decline and Ameliorates Inflammation in a Mouse Model of Alzheimer's Disease.

Front Cell Neurosci 2019 15;13:466. Epub 2019 Oct 15.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

Alzheimer's disease (AD) is one of the most common neurodegenerative disease. Accumulating evidences suggest an active role of inflammation in the pathogenesis of AD. Inflammation resolution is an active process that terminates inflammation and facilitates the restoration of inflamed tissue to homeostasis. Resolution of inflammation has been shown to be conducted by a group of specialized pro-resolving lipid mediators (SPMs) including lipoxins, resolvins, protectins, and maresins (MaRs). Recent studies have demonstrated that failure of inflammation resolution can lead to chronic inflammation and, hence, contribute to AD progression. We have previously shown that MaR1 can improve neuronal survival and increase microglial phagocytosis of Aβ. However, the effects of MaR1 on animal models of AD have not been reported. In this study, we aim to investigate the effects of MaR1 on behavioral deficits and pathological changes in a mouse model of AD. Mice received bilateral injections of Aβ protein into the hippocampus, followed by administration of MaR1 by intra-cerebroventricular injection. The behavioral changes in the mice were analyzed using Morris water maze. Immunohistochemistry, Fluoro-Jade B (FJB) staining, cytometric beads array (CBA), and western blot analysis were used to demonstrate molecular changes in the mice hippocampus and cortex. Our results showed that MaR1 treatment significantly improved the cognitive decline, attenuated microglia and astrocyte activation. In addition, we found that MaR1 decreased the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1 production induced by Aβ42 and increased the anti-inflammatory cytokines IL-2, IL-10 secretion with or without Aβ42 stimulation. Moreover, western blot results showed that MaR1 up-regulated the levels of proteins related to survival pathway including PI3K/AKT, ERK and down-regulated the levels of proteins associated with inflammation, autophagy, and apoptosis pathways such as p38, mTOR and caspase 3. To conclude, MaR1 improved the cognitive decline, ameliorated pro-inflammatory glia cells activation via improving survival, enhancing autophagy, inhibiting inflammation and apoptosis pathways. In conclusion, this study shows that inflammation resolution may be a potential therapeutic target for AD.
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http://dx.doi.org/10.3389/fncel.2019.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803487PMC
October 2019

Effect of Delayed Diagnosis of Phenylketonuria With Imaging Findings of Bilateral Diffuse Symmetric White Matter Lesions: A Case Report and Literature Review.

Front Neurol 2019 4;10:1040. Epub 2019 Oct 4.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

Phenylketonuria is a hereditary metabolic disorder due to the deficiency of tetrahydrobiopterin or phenylalanine hydroxylase. Delayed diagnoses of it manifest a progressive irreversible neurological impairment in the early years of the disease. Guthrie test and tandem mass spectrometry aided in early detection and intervention of phenylketonuria, which significantly decreased the disability of patients as well as reducing the need for diagnosis in adults. This is a case report of a 60-year-old Asian man, characterized by severe visual-spatial disorders and bilateral diffuse symmetric white matter lesions on magnetic resonance imaging, who was diagnosed as phenylketonuria with his congenital mental retardation sibling. Heterozygous mutations exist in gene encoding PAH c.1068C>A and c.740G>T. During the diagnosis, we looked up at other late-onset genetic diseases considered to occur rarely but gradually revealed similar clinical manifestations and significant white matter lesions gaining importance in guiding to correct diagnosis and treatment. We made a comprehensive review of phenylketonuria and other inherited diseases with major prevalence in adulthood with prominent white matter involvement. Our study aims to help neurologists to improve recognition of metabolism-related leukoencephalopathies without neglect of the role of congenital genetic factors.
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http://dx.doi.org/10.3389/fneur.2019.01040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788382PMC
October 2019

Effects of Follicular Helper T Cells and Inflammatory Cytokines on Myasthenia Gravis.

Curr Mol Med 2019 ;19(10):739-745

Department of Neurology, the First Bethune Hospital, Jilin University, Changchun 130021, Jilin Province, China.

Background: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. An imbalance in various T helper (Th) cells, including Th1, Th2, Th17, Th22 and follicular helper T (TFH) cells, has been found associated with immunological disturbances.

Objective: In this study, we aim to investigate the role of the Th cells in peripheral blood of MG patients.

Materials And Methods: A total of 33 MG patients and 34 age matched controls were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-Paque density gradient centrifugation assay. The proportion of TFH cells in PBMC were analyzed using flow-cytometry assay by determining the levels of cellular markers CD4, CXCR5, CD45RO, CD45RA and ICOS and PD-1. The levels of IFN-γ, IL-4, IL-17 and IL-21 in serum were analyzed by Cytometric Bead Array. The serum IL-22 level was analyzed by ELISA.

Results: The frequency of TFH cells in PBMCs was higher than those in healthy subjects and correlated to the severity of MG patients. The levels of pro-inflammatory cytokines IFN-γ, IL-17 and IL-21 were elevated in the serum of MG patients, while there were no significant differences regarding the levels of IL-4 and IL-22 between MG patients and control subjects.

Conclusion: Our findings suggest that Th cells and their cytokines balance of MG patients are involved in the clinical condition or severity of MG disease.
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http://dx.doi.org/10.2174/1566524019666190827162615DOI Listing
January 2019

Magnetic resonance imaging and magnetic resonance venography features in heat stroke: a case report.

BMC Neurol 2019 Jun 18;19(1):133. Epub 2019 Jun 18.

Department of Neurology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.

Background: Heat stroke (HS) is a critical illness that can cause multiple organ dysfunction, including damage to the central nervous system (CNS), which can be life-threatening in severe cases. Brain lesions in patients with HS who present with CNS damage have been rarely reported before, and they usually vary in different cases, hence, patients with such lesions may present a clinical challenge in terms of diagnosis and management. Cerebral venous thrombosis (CVT) is a rare cause of stroke that mostly affects young individuals and children. The pathogenesis of brain damage caused by HS is complex, and CVT may be involved in the pathogenesis of HS with CNS damage. In this manuscript, we have reported a case of a patient with HS having CVT with symmetrical lesions in the bilateral putamen, posterior limb of the internal capsule, external capsule, insular lobe, and subcortical white matter in the brain.

Case Presentation: We encountered a 48-year-old man who presented with HS in the summer season. During admission, he had a high body temperature and was in coma and shock. Then, he developed rhabdomyolysis syndrome, acute kidney and liver damage, electrolyte imbalance, and acid-base balance disorders, and his D-dimer level was elevated. After several days of anti-shock treatment, the patient's level of consciousness improved. However, he experienced a decline in vision. Cerebral magnetic resonance imaging (MRI) showed symmetrical lesions in the bilateral posterior limb of the internal capsule, putamen, external capsule, insula, and subcortical white matter, and cerebral magnetic resonance venography (MRV) showed the development of CVT. Therefore, anti-coagulation treatment was provided. After timely clinical intervention, the symptoms of the patient gradually improved.

Conclusions: This case showed that HS can cause CVT. Therefore, cerebral MRI findings in HS must be assessed; in addition, early MRV can help in the diagnosis of the disease, which can effectively improve prognosis.
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http://dx.doi.org/10.1186/s12883-019-1363-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580543PMC
June 2019

Human Serum Anti-aquaporin-4 Immunoglobulin G Detection by Cell-based Assay.

J Vis Exp 2019 04 5(146). Epub 2019 Apr 5.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University;

Anti-aquaporin-4 (AQP4) immunoglobulin G (IgG) is the core diagnostic biomarker for neuromyelitis optica spectrum disorders (NMOSD). The cell-based assay (CBA) is a widely used method to detect anti-AQP4 IgG in human serum with high sensitivity and specificity. Briefly, serum anti-AQP4 IgG is captured by AQP4-transfected cell that is fixed on the biochip then detected by a fluorescein-labelled secondary antibody. Fluorescence microscopy is utilized to visualize the fluorescence, and the intensity of fluorescence is evaluated by at least two experienced clinicians. A final diagnosis of NMOSD can be made based on the combination of anti-AQP4 IgG detection results, clinical manifestations, and neuroradiological findings. According to previous studies, CBA is more sensitive and specific than other anti-AQP4 IgG detection methods, and it can be applied to both clinical diagnosis and studies of NMOSD. The method has limitations; for example, an international scale to evaluate serum anti-AQP4 IgG titers is still lacking. Here, a detailed protocol for human serum anti-AQP4 IgG detection using CBA is described.
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http://dx.doi.org/10.3791/59014DOI Listing
April 2019

Interleukin-36 alpha levels are elevated in the serum and cerebrospinal fluid of patients with neuromyelitis optica spectrum disorder and correlate with disease activity.

Immunobiology 2019 05 1;224(3):397-401. Epub 2019 Mar 1.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China. Electronic address:

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory neurological disease characterized by longitudinally extensive transverse myelitis (LETM) and optic neuritis. Interleukin (IL)-36 is a novel cytokine of the IL-1 family that is involved in the development of inflammatory diseases. The aim of this study was to investigate the role of IL-36α in NMOSD. We retrospectively collected 73 patients, who fulfilled the 2015 criteria for NMOSD diagnosis and were admitted to the Department of Neurology of the First Hospital of Jilin University from 2015 to 2016. Fifty age and gender matched patients with non-inflammatory neurological disorders (ONNDs) were collected in the same period and served as controls. Neurological function was evaluated by the expanded disability status scale (EDSS). All participants were assessed for the annual relapse rate (ARR). Blood and cerebrospinal fluid (CSF) samples were obtained and the levels of IL-36α in the serum and CSF were analyzed by enzyme-linked immunosorbent assay (ELISA). IL-36α levels in serum and CSF were found to be significantly increased in patients with NMOSD compared to those in the controls. Furthermore, IL-36α levels in both serum and CSF were positively correlated with the EDSS score. CSF IL-36α levels were positively correlated with CSF leukocyte counts, protein concentration and immunoglobulin IgG. Our results suggest that IL-36α may be a novel biomarker for monitoring disease severity in NMOSD.
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http://dx.doi.org/10.1016/j.imbio.2019.02.008DOI Listing
May 2019

Proteomic Study of a Parkinson's Disease Model of Undifferentiated SH-SY5Y Cells Induced by a Proteasome Inhibitor.

Int J Med Sci 2019 1;16(1):84-92. Epub 2019 Jan 1.

Departments of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin Province, China.

Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study.

Methods: Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching.

Results: The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process.

Conclusions: Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.
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http://dx.doi.org/10.7150/ijms.28595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332475PMC
April 2019

Resolution of inflammation in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2019 Jan 2;27:34-41. Epub 2018 Oct 2.

Department of Neurology, The First Hospital of Jilin University, Xinmin Street 71#, Changchun 130021, China. Electronic address:

Background: Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of neuroinflammatory disorders associated with autoimmune antibodies against aquaporin-4 (AQP4). Accumulating evidence suggests that inflammation is involved in NMOSD pathogenesis. Resolution of inflammation, which is a highly regulated process mediated by specialized pro-resolving lipid mediators (SPMs) is important to prevent over-responsive inflammation. Deficiency in resolution of inflammation may lead to or accelerates inflammatory diseases. However, whether resolution of inflammation is impaired in NMOSD is not known. The objective of this study was to analyze the levels of SPMs in the serum and cerebrospinal fluid (CSF) of NMOSD patients, and to explore the roles of SPMs in clinical features of NMOSD.

Methods: Thirty-five patients with NMOSD, 34 patients with multiple sclerosis, and 36 patients with non-inflammatory neurological diseases were enrolled in this study. Pro-resolving mediators including Annexin A1 (ANXA1) and resolvin D1 (RvD1), as well as pro-inflammatory lipid mediator leukotriene B4 (LTB4) levels were analyzed by enzyme-linked immunosorbent assay. Pro- and anti-inflammatory cytokines as well as chemokine levels were analyzed using cytometric beads array (CBA).

Results: Our results showed RvD1 levels were significantly decreased, whereas LTB4 levels were significantly increased in the CSF of NMOSD patients. AQP4-IgG titer was negatively correlated with RvD1 levels in the CSF of NMOSD patients.

Conclusions: Decreased RvD1 levels indicate impaired resolution of inflammation in NMOSD patients. AQP4-IgG may contribute to increased inflammation and lead to unresolved inflammation in NMOSD.
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http://dx.doi.org/10.1016/j.msard.2018.09.040DOI Listing
January 2019

Blood Brain Barrier Permeability Could Be a Biomarker to Predict Severity of Neuromyelitis Optica Spectrum Disorders: A Retrospective Analysis.

Front Neurol 2018 7;9:648. Epub 2018 Aug 7.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

Blood-brain barrier (BBB) pathology exists in neuromyelitis optica spectrum disorders (NMOSD). However, the clinical use of BBB permeability, such as predicting disease severity of NMOSD, has rarely been studied in a large cohort of patients. The current study explored the association between BBB permeability and clinical parameters in order to assess if BBB permeability could be a biomarker to predict disease severity and clinical characteristics of NMOSD. Among 69 enrolled NMOSD patients, 47 with albumin index over 5 × 10 were assigned to the increased BBB permeability group, and the remaining 22 were to the normal BBB permeability group. Disease severity was assessed using the Expanded Disability Status Scale (EDSS). Patients in the increased BBB permeability group had significantly higher EDSS scores, anti-aquporin-4 immunoglobulin G titers, more dense cerebrospinal fluid protein concentrations, white blood cell counts, myelin basic protein levels and more dense complement 3 concentrations than found in the comparative normal BBB permeability group. The albumin index was positively correlated to the length of lesions in spinal cord. BBB permeability was associated with clinical features, laboratory results and radiological data of NMOSD patients, and may be a potential biomarker to predict disease severity and clinical characteristics of NMOSD.
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http://dx.doi.org/10.3389/fneur.2018.00648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090143PMC
August 2018

Roles of Specialized Pro-Resolving Lipid Mediators in Cerebral Ischemia Reperfusion Injury.

Front Neurol 2018 31;9:617. Epub 2018 Jul 31.

Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China.

Ischemic stroke contributes to ~80% of all stroke cases. Recanalization with thrombolysis or endovascular thrombectomy are currently critical therapeutic strategies for rebuilding the blood supply following ischemic stroke. However, recanalization is often accompanied by cerebral ischemia reperfusion injury that is mediated by oxidative stress and inflammation. Resolution of inflammation belongs to the end stage of inflammation where inflammation is terminated and the repair of damaged tissue is started. Resolution of inflammation is mediated by a group of newly discovered lipid mediators called specialized pro-resolving lipid mediators (SPMs). Accumulating evidence suggests that SPMs decrease leukocyte infiltration, enhance efferocytosis, reduce local neuronal injury, and decrease both oxidative stress and the production of inflammatory cytokines in various and models of ischemic stroke. In this review, we summarize the mechanisms of reperfusion injury and the various roles of SPMs in stroke therapy.
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http://dx.doi.org/10.3389/fneur.2018.00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090140PMC
July 2018

Can inflammation be resolved in Alzheimer's disease?

Ther Adv Neurol Disord 2018 9;11:1756286418791107. Epub 2018 Aug 9.

Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, Center for Alzheimer Research, Sweden.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and dementia. Accumulating evidence suggests that inflammation is involved in the pathogenesis of AD. Epidemiological studies suggest that use of anti-inflammatory drugs is associated with a lower incidence of AD. However, clinical trials with anti-inflammatory drugs have not been successful. Recent studies have shown that inflammation is resolved by a process that is mediated by a group of lipid mediators, so called specialized pro-resolving lipid mediators (SPMs). Unlike anti-inflammatory strategies, which usually involve inhibition of the synthesis of inflammatory mediators, stimulating the resolution of inflammation is aimed at ending inflammation in a similar fashion as under normal physiological conditions. We have previously shown that pathways of resolution are impaired in AD. Moreover, we found that SPMs can improve neuronal survival and increase microglial phagocytosis of amyloid beta (Aβ) in studies, indicating that stimulating resolution of inflammation may be a potential therapeutic target in AD. In this review, we summarize recent findings regarding resolution of inflammation in AD. We also discuss possible strategies to stimulate the resolution of inflammation in AD, specifically focusing on signaling pathways, including SPMs, their receptors and enzymes involved in their formation.
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http://dx.doi.org/10.1177/1756286418791107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088473PMC
August 2018

Longitudinally extensive transverse myelitis with pulmonary tuberculosis: Two case reports.

Medicine (Baltimore) 2018 Jan;97(3):e9676

Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun, China.

Rationale: Longitudinally extensive transverse myelitis (LETM) is characterized by contiguous inflammatory lesions of spinal cord extending to ≥3 vertebral segments. The etiology of LETM is complicated, including various infection, autoimmune disease, and so on. Neuromyelitis optic spectrum disorder (NMOSD) is the most common cause of LETM. Several case reports have suggested the associations between NMOSD and pulmonary tuberculosis (PTB).

Patient Concerns: Patient 1, a 20-year-old woman who had a past history of PTB, presented with weakness, numbness, and pain in the limbs. The serum anti-aquaporin-4 antibody (AQP4-Ab) was strongly positive, and the magnetic resonance imaging (MRI) scan of cervical and thoracic spinal cord after admission to the hospital revealed hyperintensity lesions extending from C3 to T8 on T2-weighted (T2W) image, T1-weighted (T1W) image, and fluid-attenuated inversion recovery (FLAIR) image. Patient 2, a 21-year-old woman who had a past medical history of PTB without receiving any treatment, presented for numbness in bilateral lower limbs and in the chest. The anti-AQP4-Ab was negative both in the serum and in the cerebral spinal fluid (CSF) of the patient. The MRI scan during hospitalization of cervical and thoracic spinal cord revealed diffuse hyperintense signal extending C3 to T11 on T2W and FLAIR images and hypointense signal on T1W image.

Diagnosis: The first patient was diagnosed with anti-AQP4-Ab positive NMOSD, while the second case was an anti-AQP4-Ab negative LETM patient.

Interventions: Both of the patients received a combination of corticosteroid and anti-tuberculosis (isonicotinyl hydrazide 0.3 g/d, rifampin 0.45 g/d, pyrazinamide 1 g/d, and ethambutol 1 g/d) treatment.

Outcomes: The patients were followed up for up to 1 year. The Expanded Disability Status Scale (EDSS) of both patients were decreased and the lesion size in the spinal cord was significantly reduced at the time point of the follow-up.

Lessons: Combination of anti-tuberculosis and corticosteroid treatment may have better prognosis for patient of LETM with PTB.
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http://dx.doi.org/10.1097/MD.0000000000009676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779784PMC
January 2018

Autoimmune encephalitis positive for both anti-γ-aminobutyric acid B receptor and anticollapsin response-mediator protein 5 antibodies: A case report.

Medicine (Baltimore) 2018 Jan;97(3):e9574

Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin, China.

Rationale: Autoimmune encephalitis (AE) is a heterogeneous group of recently identified disorders. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with proper immunotherapy in some patients with AE. Antineuronal antibodies have been discovered in patients' serum and cerebrospinal fluid (CSF). However, AE with multiple antineuronal antibodies is rare. To date, there are no published reports of AE with both anti-γ-aminobutyric acid B receptor (GABABR) and anticollapsin response-mediator protein 5 (CV2) antibodies.

Patient Concerns: We describe a 46-year-old man who presented with seizures, working memory deficits, and visual hallucinations. We detected anti-CV2 and anti-GABABR antibodies in his serum and CSF. Brain magnetic resonance imaging (MRI) revealed patchy abnormal signals in his left temporal lobe and hippocampus. The patient's symptoms improved after receiving intravenous immunoglobulin injections and glucocorticoids, but his condition relapsed within 4 months, and he was readmitted to our hospital. Repeated MRI scans revealed new lesions in his right temporal lobe and hippocampus.

Diagnosis: The AE diagnosis was established from the results of the preliminary physical examination, the laboratory tests, and the imaging findings.

Interventions: The patient received intravenous immunoglobulins and glucocorticoids.

Outcomes: We followed the patient for 9 months from the date of the patient's second hospital discharge. He experienced no seizures during this period, but his short-term memory deficits and visual hallucinations were not completely alleviated.

Lessons: Coexisting anti-CV2 and anti-GABABR antibodies may have synergistic effects and worsen the clinical syndrome. AE with multiple antineuronal antibodies may be relapse-prone. Further studies investigating the relationship between anti-CV2 and anti-GABABR antibodies are warranted.
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http://dx.doi.org/10.1097/MD.0000000000009574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779748PMC
January 2018

Cerebral venous thrombosis originating from internal jugular vein outflow impairment: A case report.

Medicine (Baltimore) 2017 Dec;96(48):e8975

Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin, China.

Rationale: Cerebral venous thrombosis (CVT) comprises a group of cerebral vascular diseases resulting from cerebral venous outflow obstruction caused by various etiologies. The etiology of CVT is complex, including infectious and noninfectious factors. The diagnosis is difficult. As a result, many patients are misdiagnosed or never diagnosed. This patient was diagnosed with CVT due to unilateral internal jugular vein compression.

Patient Concerns: In this report, we present a case of acute onset CVT in a 15-year-old female patient who presented with a headache, nausea, and vomiting as the main clinical manifestations.

Interventions: This patient was administered with conventional anticoagulants and treated for dehydration, but the effect of conventional therapy was not obvious.

Outcomes: We recommended that this patient undergo left local decompression of the internal jugular vein to inhibit the thrombosis. But regretfully, due to economic reasons and surgical risk, the patient and her mother refused operation.

Lessons: This case report demonstrates the importance of considering jugular vein lesions as an etiology of CVT. Furthermore, computed tomography venography of the jugular vein and jugular vein ultrasound were instrumental in detecting the abnormal structure of the jugular vein and hemodynamic changes.
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http://dx.doi.org/10.1097/MD.0000000000008975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728807PMC
December 2017

Hashimoto's encephalitis associated with AMPAR2 antibodies: a case report.

BMC Neurol 2017 Feb 21;17(1):37. Epub 2017 Feb 21.

Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Xinmin Street No 71, Changchun, 130000, China.

Background: Hashimoto's encephalitis (HE) is a rare neurological complication of Hashimoto's thyroiditis (HT), while limbic encephalitis (LE) is an autoimmune inflammatory disorder frequently associated with anti-neuronal antibodies. The glutamate receptor α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) is important for synaptic transmission, memory, and learning. The etiology of HE remains unclear. We present a case of HE with antibodies to AMPAR2 both in the serum and cerebrospinal fluid.

Case Presentation: The patient presented with progressive memory loss and subsequently went into a coma. Magnetic resonance imaging revealed temporal lobe and hippocampal lesions, while the electrocardiogram showed paroxysmal delta waves. Elevated serum levels of antibodies against thyroid globulin, thyroid peroxidase, and thyroid stimulating receptor were also noted. Ultrasonography showed enlargement of the thyroid gland. Therefore, the diagnosis was established as HE. Both the CSF and serum samples of the patient tested positive for antibodies to the cell-surface antigen AMPAR2. Intravenous injection of immunoglobulin followed by dexamethasone treatment resulted in recovery from the coma. Follow-up examination three months later showed some improvement of memory. To our knowledge, this is the first report on the detection of AMPAR2 antibodies in HE.

Conclusions: Our findings suggest that antibodies to AMPAR2 may be involved in the pathogenesis of HE. Elevated levels of thyroid antibodies possibly cause immune dysfunction, leading to the production of anti-AMPAR2 antibodies that are detrimental to the neurons. We believe that encephalitis patients with thyroid abnormalities should undergo screening for anti-neuronal antibodies, and early immune therapy may improve prognosis.
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http://dx.doi.org/10.1186/s12883-017-0823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320737PMC
February 2017

Aquaporin-4 positive neuromyelitis optica spectrum disorders secondary to thrombopenic purpura: A case report.

Medicine (Baltimore) 2017 Jan;96(2):e5792

aDepartment of Neurology, the First Hospital of Jilin University bDepartment of Ophthalmology, the Second Hospital of Jilin University, Changchun cCurrent address: Department of Life Sciences, the National Natural Science Foundation of China, Beijing, China.

Rationale: Neuromyelitis optica spectrum disorders (NMOSD) is considered as an immune-mediated disorder in the central nervous system (CNS). Numerous autoimmune diseases are frequently complicated with NMOSD and distinct clinical characteristics are noted in NMOSD patients with other autoimmune diseases. However, to our best knowledge, co-occurrence of NMOSD and thrombopenic purpura is rarely identified.

Patient Concerns: We presented a rare case of a 72-year-old female with 6-year history of thrombopenic purpura, and 1-month history of blurred vision as well as chest zonethesia. Anti-aquaporin-4 (AQP4) antibodies was positive in the serum of the patient.

Diagnoses: With the addition of laboratory findings, iconography findings and physical examination results, the diagnosis of NMOSD was established according to the most recent diagnostic criteria.

Interventions And Outcomes: With the treatment of intravenous immunoglobulin (IVIg), the patient felt better at discharge without changing of expanded disability status scale (EDSS) score.

Lessons: The case indicates that NMOSD could co-occur with thrombopenic purpura. The disturbance of immune system balance may explain this overlap. Further studies are warranted to reveal the mechanism and to explore whether patients with NMOSD with and without thrombopenic purpura have distinct clinical feature, drug responsiveness or prognosis.
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http://dx.doi.org/10.1097/MD.0000000000005792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266166PMC
January 2017

Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP-activated protein kinase-dependent autophagy in a rat cerebral ischemic/reperfusion injury model.

J Neurochem 2017 03 12;140(5):799-813. Epub 2017 Jan 12.

Institute of Neuroscience Center and Neurology Department, The First Affiliated Hospital of Jilin University, Changchun, Jilin, China.

Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic-reperfusion (I/R) injury model to determine whether AMP-activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KCl solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine (3-MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1 and the p-AMPK (Thr )/AMPK ratio at 12 h and decreased P62 and p-P70S6K (Thr ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down-regulated the LC3-II, p-AMPK (Thr )/AMPK and ULK1 levels, up-regulated the P62 and p-P70S6K (Thr ) levels induced by CSD. The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke.
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http://dx.doi.org/10.1111/jnc.13922DOI Listing
March 2017

Relapsing-remitting lesions in a woman with progressive hemifacial atrophy and chronic hepatitis B virus infection: A case report.

Medicine (Baltimore) 2016 Nov;95(47):e5390

Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Xinmin, Changchun, China Department of Neurobiology, Care Sciences & Society, Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm, Sweden.

Introduction: Progressive hemifacial atrophy (PHA) is a rare disorder characterized by unilateral facial atrophy affecting the skin, subcutaneous tissue, and fat, muscle, and osteocartilagenous structures creating a sunken hemiface appearance.Etiopathogenesis of PHA is poorly understood; no definitive treatment is currently available.

Clinical Findings: We report a 41-year-old woman with PHA who showed an uncharacteristic "relapsing-remitting" evolution of brain lesions and was seropositive for hepatitis B virus (HBV). She presented with a history of recurrent tonic-clonic seizures. Magnetic resonance imaging (MRI) showed progressive atrophy and multiple white matter lesions in the left side of the brain. Interestingly, the serial MRI examination (4 MRI scans over a period of 9 years) showed a "relapsing-remitting" pattern of brain lesions akin to that observed in a subtype of multiple sclerosis. Autoimmune-related investigations revealed increased serum levels of immunoglobulin (Ig) G, anti-nuclear antibody (ANA), and γ-IgG. Infection is considered as one of the possible causes of PHA. However, the association of peripheral infection such as HBV infection with PHA has not been reported.

Conclusion: Our experience with this case suggests that PHA may have a relapsing-remitting disease course. Autoimmune inflammatory response to chronic HBV infection may have triggered the relapse in this case. This case underlines a novel etiopathogenetic mechanism of PHA.
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http://dx.doi.org/10.1097/MD.0000000000005390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134867PMC
November 2016

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis.

Mol Neurobiol 2016 May 9;53(4):2733-49. Epub 2015 Dec 9.

Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Karolinska Institutet, SE-141 86, Stockholm, Sweden.

Inflammation in the brain is a prominent feature in Alzheimer's disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study, we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1), and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, resolvin D1 (RvD1), and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated β-amyloid (Aβ)42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aβ42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.
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http://dx.doi.org/10.1007/s12035-015-9544-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824659PMC
May 2016

Differential regulation of resolution in inflammation induced by amyloid-β42 and lipopolysaccharides in human microglia.

J Alzheimers Dis 2015 ;43(4):1237-50

Karolinska Institutet, Department of Neurobiology, Care Sciences & Society, Section of Neurodegeneration, Novum, Huddinge, Stockholm, Sweden.

Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-β (Aβ) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of the resolution cascade. In this pursuit, we exposed microglia to Aβ42, and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (α7nAChR) and peroxisome proliferator-activated receptor (PPAR)-δ whereas Aβ42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Aβ42. Further studies may prove if Aβ42-induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD.
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http://dx.doi.org/10.3233/JAD-141233DOI Listing
August 2015

Resolution of inflammation is altered in Alzheimer's disease.

Alzheimers Dement 2015 Jan 12;11(1):40-50.e1-2. Epub 2014 Feb 12.

Department of Neurobiology, Care Sciences and Society, Section of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD).

Methods: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF).

Results: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores.

Conclusions: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
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http://dx.doi.org/10.1016/j.jalz.2013.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275415PMC
January 2015

Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model.

J Cell Mol Med 2013 Nov 12;17(11):1434-43. Epub 2013 Sep 12.

Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Geriatric Clinic Res Lab, Stockholm, Sweden; Department of Neurology, First Hospital of Jilin University, Changchun, China.

Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-β was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.
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http://dx.doi.org/10.1111/jcmm.12123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117556PMC
November 2013