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      Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

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          Abstract

          Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

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          Most cited references323

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          Neurotoxic reactive astrocytes are induced by activated microglia

          A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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            A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

            Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
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              Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

              Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.
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                Author and article information

                Contributors
                e.newcombe@uq.edu.au
                j.camatsperna@uq.edu.au
                m.lopesdasilva@uq.edu.au
                n.valmas@uq.edu.au
                t.tee@uq.edu.au
                rodrigo.medeiros@neurula.org , r.medeiros@uq.edu.au
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                24 September 2018
                24 September 2018
                2018
                : 15
                : 276
                Affiliations
                [1 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Neurula Laboratory, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, , The University of Queensland, ; Building 79, Brisbane, 4072 QLD Australia
                [2 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Queensland Brain Institute, , The University of Queensland, ; Brisbane, 4072 QLD Australia
                [3 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Centre for Stem Cell Ageing and Regenerative Engineering, , The University of Queensland, ; Brisbane, 4072 QLD Australia
                Author information
                http://orcid.org/0000-0002-9399-7852
                Article
                1313
                10.1186/s12974-018-1313-3
                6154824
                30249283
                905af427-ecff-45b7-8693-8b0810153f2f
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 July 2018
                : 11 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: GNT1128436
                Award ID: GNT1129192
                Award ID: GNT1139469
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                alzheimer’s disease,microglia,aging,neuroinflammation,apoe4,trem2,cd33,diabetes,tbi,obesity
                Neurosciences
                alzheimer’s disease, microglia, aging, neuroinflammation, apoe4, trem2, cd33, diabetes, tbi, obesity

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