Monday, October 13, 2014

Inflammation, the Immune System, and the Brain - New Models of Disease

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In recent years, science is finally beginning to grasp the obvious fact that the human body is a system, so that when something goes wrong in one part of the organism, it has effects in other parts of the organism as well. The most obvious example of this is the new focus on the microbiome (the enteric nervous system and the flora that inhabit it) and its relation to physical and mental health.

The microbiome is also where the heart of the immune system resides. When the "gut" is not healthy, the immune system is not healthy, which leads to higher levels of inflammation.

One of the key issues researchers are focusing on is inflammation - a normal and healthy response to a wound or exposure to a pathogen, but not so healthy when levels of inflammation remain elevated for long periods of time (which can happen when we are under chronic stress conditions).

Inflammation has been linked to Alzheimer's Disease, diabetes, depression, damaged memory retrieval, schizophrenia, and many other physical and psychological issues.

Here are some recent articles on the intersection of the immune system and mental health and the role of inflammation, and specifically neuroinflammation, on the brain and the mind. These are arranged from easiest to read to the more technical research at the bottom of the post.

Mind and body: Scientists identify immune system link to mental illness

Date: August 13, 2014
Source: University of Cambridge

Summary:
Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research that suggests a role for the immune system in mental illness. The study indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.

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A team of scientists led by the University of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children -- also known as Children of the 90s -- taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. The team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the 'high' group were nearly two times more likely to have experienced depression or psychosis than those in the 'low' group.
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Inflammation in Pregnancy Strongly Linked to Schizophrenia


Caroline Cassels | Science Codex
September 04, 2014

Elevated levels of C-reactive protein in pregnant women are strongly linked to an increased risk for schizophrenia in offspring, new research shows.

A nested case-control study showed that increasing maternal levels of C-reactive protein, a well-established and reliable marker of inflammation, were associated with a nearly 60% increased risk for schizophrenia in children. The finding remained significant after adjusting for a wide range of potential confounders, including parental history of mental illness.

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implication for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders," the authors, led by Sarah Cannetta, PhD, Columbia University and New York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.
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Inflammation in Pregnancy Strongly Linked to Schizophrenia


Caroline Cassels | Medscape
September 04, 2014

Elevated levels of C-reactive protein in pregnant women are strongly linked to an increased risk for schizophrenia in offspring, new research shows.

A nested case-control study showed that increasing maternal levels of C-reactive protein, a well-established and reliable marker of inflammation, were associated with a nearly 60% increased risk for schizophrenia in children. The finding remained significant after adjusting for a wide range of potential confounders, including parental history of mental illness.

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implication for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders," the authors, led by Sarah Cannetta, PhD, Columbia University and New York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.
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The common inflammatory etiology of depression and cognitive impairment: a therapeutic target


David J Allison and David S Ditor

Journal of Neuroinflammation (2014, Sep 2); 11:151 

doi:10.1186/s12974-014-0151-1 

Abstract

Chronic inflammation has been shown to contribute to the development of a wide variety of disorders by means of a number of proposed mechanisms. Depression and cognitive impairment are two such disorders which may share a closely linked inflammatory etiology. The ability of inflammatory mediators to alter the activity of enzymes, from key metabolic pathways, may help explain the connection between these disorders. The chronic up-regulation of the kynurenine pathway results in an imbalance in critical neuroactive compounds involving the reduction of tryptophan and elevation of tryptophan metabolites. Such imbalances have established implications in both depression and cognitive impairment. This may implicate the immune system as a potential therapeutic target in the treatment of these disorders. The most common treatment modalities currently utilized, involve drug interventions which act on downstream targets. Such treatments help to reestablish protein balances, but fail to treat the inflammatory basis of the disorder. The use of anti-inflammatory interventions, such as regular exercise, may therefore, contribute to the effectiveness of current drug interventions in the treatment of both depression and cognitive impairment.
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Calcineurin and glial signaling: neuroinflammation and beyond


Jennifer L Furman and Christopher M Norris


Journal of Neuroinflammation (2014, Sep 10); 11:158 

doi:10.1186/s12974-014-0158-7
 

Abstract

Similar to peripheral immune/inflammatory cells, neuroglial cells appear to rely on calcineurin (CN) signaling pathways to regulate cytokine production and cellular activation. Several studies suggest that harmful immune/inflammatory responses may be the most impactful consequence of aberrant CN activity in glial cells. However, newly identified roles for CN in glutamate uptake, gap junction regulation, Ca2+ dyshomeostasis, and amyloid production suggest that CN’s influence in glia may extend well beyond neuroinflammation. The following review will discuss the various actions of CN in glial cells, with particular emphasis on astrocytes, and consider the implications for neurologic dysfunction arising with aging, injury, and/or neurodegenerative disease.
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Up-regulation of miRNA-146a in progressive, age-related inflammatory neurodegenerative disorders of the human CNS


Peter N. Alexandrov, Prerna Dua and Walter J. Lukiw
Frontiers in Neurology: Neurogenomics; (2014, Sep 29)
doi: 10.3389/fneur.2014.00181
Overview

The human brain- and retinal-resident microRNA-146a (miRNA-146a) is an inducible, NF-kB-regulated small non-coding RNA (sncRNA) whose increased expression is associated with pro-inflammatory neurodegeneration in Alzheimer’s disease (AD), age-related macular degeneration (AMD), and prion disease (PrD). In AD, AMD, and PrD miRNA-146a modulates the innate-immune response, inflammation, and the microglial activation state. This short paper will review and comment on the role of miRNA-146a signaling and how it underlies common molecular-pathogenetic mechanisms in each of these progressive, age-related neurological disorders for which there are currently no effective treatment or cure.
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