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      Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer’s Disease

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          Abstract

          More than 300 years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed “ animalcules,” examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high-throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer’s disease (AD) is the most common cause of dementia characterized by a progressive decline in memory and thinking severe enough to interfere with daily life. Despite the great progress in linking genetic risk factors with AD pathogenesis, treatments targeted at AD pathology and its modifiers have not yet resulted in a disease-modifying therapy. There is mounting evidence that the gut microbiota interacts with AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis—the gut microbiota has gone from being the forgotten organ to a potential key player in the AD pathology.

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          Most cited references37

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          Quorum sensing: cell-to-cell communication in bacteria.

          Bacteria communicate with one another using chemical signal molecules. As in higher organisms, the information supplied by these molecules is critical for synchronizing the activities of large groups of cells. In bacteria, chemical communication involves producing, releasing, detecting, and responding to small hormone-like molecules termed autoinducers . This process, termed quorum sensing, allows bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to changes in the number and/or species present in a community. Most quorum-sensing-controlled processes are unproductive when undertaken by an individual bacterium acting alone but become beneficial when carried out simultaneously by a large number of cells. Thus, quorum sensing confuses the distinction between prokaryotes and eukaryotes because it enables bacteria to act as multicellular organisms. This review focuses on the architectures of bacterial chemical communication networks; how chemical information is integrated, processed, and transduced to control gene expression; how intra- and interspecies cell-cell communication is accomplished; and the intriguing possibility of prokaryote-eukaryote cross-communication.
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            A microbial symbiosis factor prevents intestinal inflammatory disease.

            Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.
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              Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

              Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
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                Author and article information

                Contributors
                Role: Decision Editor
                Journal
                J Gerontol A Biol Sci Med Sci
                J. Gerontol. A Biol. Sci. Med. Sci
                gerona
                The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
                Oxford University Press (US )
                1079-5006
                1758-535X
                June 2020
                18 November 2019
                18 November 2019
                : 75
                : 7
                : 1232-1241
                Affiliations
                Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine , St. Louis, Missouri
                Author notes
                Address correspondence to: David M. Holtzman, MD, Department of Neurology, Washington University in St. Louis, 660 S. Euclid, Box 8111, St. Louis, MO 63110. E-mail: holtzman@ 123456wustl.edu
                Author information
                http://orcid.org/0000-0003-0315-4489
                Article
                glz262
                10.1093/gerona/glz262
                7302187
                31738402
                370bbe01-87c9-46eb-aa9c-332947047e4f
                © The Gerontological Society of America 2019.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 28 April 2019
                : 28 April 2019
                : 26 November 2019
                Page count
                Pages: 10
                Funding
                Funded by: Good Ventures;
                Categories
                Special Issue: The Gut Microbiome and Aging
                AcademicSubjects/MED00280
                AcademicSubjects/SCI00960

                Geriatric medicine
                microbiome,bacteria,tau,amyloid,neurodegeneration
                Geriatric medicine
                microbiome, bacteria, tau, amyloid, neurodegeneration

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