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The roles of inflammation and immune mechanisms in Alzheimer's disease.

ABSTRACT: The Alzheimer's Association's Research roundtable met in April 2015 to explore the role of neuroinflammatory mechanisms in the progression of Alzheimer's disease (AD). The ability of innate immune cells, particularly microglia and astrocytes, to mediate neuroinflammation in AD has been implicated as a significant contributor to disease pathogenesis. Adaptive immunity, which plays an important role in responding to injury and some diseases of the central nervous system, may contribute to neuroinflammation in AD as well. Communication between the central and peripheral immune systems may also be important in AD. An increased understanding of the physiology of the innate immune system may aid the identification of new therapeutic targets or mechanisms. The development of predictive animal models and translatable neuroinflammation biomarkers for AD would also facilitate the advancement of novel treatments for innate immunity. Important challenges impeding the advancement of new therapeutic agents and strategies to overcome them were discussed.

SUBMITTER: Van Eldik LJ

PROVIDER: S-EPMC5644267 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The roles of inflammation and immune mechanisms in Alzheimer's disease.

Van Eldik Linda J LJ Carrillo Maria C MC Cole Patricia E PE Feuerbach Dominik D Greenberg Barry D BD Hendrix James A JA Kennedy Matthew M Kozauer Nick N Margolin Richard A RA Molinuevo José L JL Mueller Reinhold R Ransohoff Richard M RM Wilcock Donna M DM Bain Lisa L Bales Kelly K

Alzheimer's & dementia (New York, N. Y.) 20160530 2

The Alzheimer's Association's Research roundtable met in April 2015 to explore the role of neuroinflammatory mechanisms in the progression of Alzheimer's disease (AD). The ability of innate immune cells, particularly microglia and astrocytes, to mediate neuroinflammation in AD has been implicated as a significant contributor to disease pathogenesis. Adaptive immunity, which plays an important role in responding to injury and some diseases of the central nervous system, may contribute to neuroinf ...[more]

PMID: 29067297

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Project description:Inflammatory bowel disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and malnutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either (i) increasing its potential to switch to a regulatory M2 phenotype or (ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of PPARgamma mutation with IBD is its ability to mediate the M1 to M2 switch.

Dataset Information

The roles of inflammation and immune mechanisms in Alzheimer's disease.

Publications

The roles of inflammation and immune mechanisms in Alzheimer's disease.

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