Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation

Bute Medical School, University of St. Andrews Fife, Scotland, UK.
Frontiers in Psychiatry 05/2011; 2(3):27. DOI: 10.3389/fpsyt.2011.00027
Source: PubMed


Autism Spectrum Condition (ASC) is recognised as having an inflammatory component. Post mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebro-spinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements and of NF-kB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centres: London Brain Bank, Kings College London, UK (ASC: N=3, controls: N=4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: N=6, controls: N=5). The hypothesis was that concentrations of NF-kB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e. acidification). Neurons, astrocytes and mircroglia all demonstrated increased extranuclear and nuclear translocated NF-kB p65 expression in samples of brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenised samples demonstrated a 0.98 unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-kB in mature microglia. Acridine orange staining localised pH reductions to lysosomal compartments. In summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients with ASC as part of a putative molecular cascade leading to inflammation that is potentially responsible for the associated behavioural and clinical symptoms.

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Available from: Adam M H Young, Oct 03, 2015
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    • "Neuroimaging supports these histological findings (Suzuki et al., 2013). Evidence for disruption in immune regulation is supported by elevations in proinflammatory cytokines in brain tissue from the frontal (Li et al., 2009), cingulate (Vargas et al., 2005), and cerebellum (Wei et al., 2011) and in CSF (Vargas et al., 2005; Chez et al., 2007) derived from individuals with ASD and elevations in the expression of genes regulating proinflammatory pathways in the temporal (Garbett et al., 2008) and frontal (Young et al., 2011) areas in individuals with ASD. Although some studies have reported some negative or inconsistent results (Vargas et al., 2005; Zimmerman et al., 2005; Malik et al., 2011b), the majority of studies point to an activation of the innate immune system in the brain of individuals with ASD and some of the findings, particularly the cytokine elevations, parallel abnormal elevations in cytokines reported in non-CNS tissue in children with ASD. "
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    ABSTRACT: Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations. Therefore, ASD has traditionally been framed as a behavioral disorder. However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD.
    Frontiers in Physiology 04/2014; 5:150. DOI:10.3389/fphys.2014.00150 · 3.53 Impact Factor
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    • "Isoleucine 0 , 3 , 2 ↔ Serum, plasma 5 (Croonenberghs et al., 2000; Aldred et al., 2003; Arnold et al., 2003; Adams et al., 2011; Shimmura et al., 2011) Lactate 6 , 0 , 1 ↔ Serum, plasma 7 (Moreno et al., 1992; László et al., 1994; Chugani et al., 1999; Oliveira et al., 2005; Weissman et al., 2008; Al-Mosalem et al., 2009; Giulivi et al., 2010) Leptin 6 , 0 , 1 ↔ Plasma, brain 4 (7 projects) (Vargas et al., 2005; Ashwood et al., 2008; Blardi et al., 2009; Blardi et al., 2010) Macrophage inflammatory protein-1α 0 , 1 , 2 ↔ Plasma 3 (Ashwood et al., 2010; Manzardo et al., 2012) Macrophage inflammatory protein-1β 1 , 1 , 1 ↔ Plasma 3 (Ashwood et al., 2010; Manzardo et al., 2012) Mitochondrial electron transport chain V 3 , 6 , 0 ↔ Brain 3 (9 projects) (Purcell et al., 2001; Sajdel-Sulkowska et al., 2011; Young et al., 2011) Oxytocine receptor (OXTR) 0 , 1 , 1 ↔ Brain 2 (Purcell et al., 2001; Fatemi et al., 2005) Oxytocin 0 , 3 , 0 ↔ Plasma 3 (Modahl et al., 1998; Green et al., 2001; Al-Ayadhi, 2005) Prolactin (PRL) 1 , 0 , 2 ↔ Serum, plasma 3 (Curin et al., 2003; Iwata et al., 2011) "
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    ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of disorders which have complex behavioural phenotypes. Although ASD is a highly heritable neuropsychiatric disorder, genetic research alone has not provided a profound understanding of the underlying causes. Recent developments using biochemical tools such as transcriptomics, proteomics and cellular models, will pave the way to gain new insights into the underlying pathological pathways. This review addresses the state-of-the-art in the search for molecular biomarkers for ASD. In particular, the most important findings in the biochemical field are highlighted and the need for establishing streamlined interaction between behavioural studies, genetics and proteomics is stressed. Eventually, these approaches will lead to suitable translational ASD models and, therefore, a better disease understanding which may facilitate novel drug discovery efforts in this challenging field.
    The International Journal of Neuropsychopharmacology 11/2013; 17(04):1-23. DOI:10.1017/S146114571300117X · 4.01 Impact Factor
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    • "NF-κB is an important gene involved in the mediation of inflammation and apoptosis, indicating that pro-inflammatory processes in autism could be up-regulated by this transcriptional factor. Increased NF-κB expression levels were found also in post-mortem samples of orbito-frontal cortex from autistic patients, further indicating a neuro-inflammatory condition (Young et al., 2011). Peripheral blood mononuclear cells (PBMCs) demonstrate significant aberrations in autistic children (Siniscalco et al., 2012c). "
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    ABSTRACT: Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders.
    Frontiers in Immunology 06/2013; 4:140. DOI:10.3389/fimmu.2013.00140
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