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      Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

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          Abstract

          Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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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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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/1004140/overview
                URI : http://loop.frontiersin.org/people/653682/overview
                URI : http://loop.frontiersin.org/people/125027/overview
                URI : http://loop.frontiersin.org/people/404904/overview
                URI : http://loop.frontiersin.org/people/74869/overview
                URI : http://loop.frontiersin.org/people/54366/overview
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                05 November 2020
                2020
                : 11
                : 560375
                Affiliations
                [1] 1The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China , Chengdu, China
                [2] 2Tissue Repair and Cytoprotection Research Group, Center for Genetic Engineering and Biotechnology , Havana, Cuba
                [3] 3Cuban Neurosciences Center, Cubanacan , Havana, Cuba
                [4] 4Applied Mathematics Department, Institute of Mathematics, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil
                Author notes

                Edited by: Khalid Siddiqui, King Saud University, Saudi Arabia

                Reviewed by: P. Hemachandra Reddy, Texas Tech University Health Sciences Center, United States; Jitendra Kumar, University of Alberta, Canada

                This article was submitted to Diabetes: Molecular Mechanisms, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2020.560375
                7674493
                33224105
                8debee53-981e-4a79-af32-62ffb8a9ad43
                Copyright © 2020 Berlanga-Acosta, Guillén-Nieto, Rodríguez-Rodríguez, Bringas-Vega, García-del-Barco-Herrera, Berlanga-Saez, García-Ojalvo, Valdés-Sosa and Valdés-Sosa.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 May 2020
                : 13 August 2020
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 282, Pages: 22, Words: 18884
                Funding
                Funded by: University of Electronic Science and Technology of China 10.13039/501100005408
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                alzheimer's disease,neurodegeneration,β-amyloid plaques,neurofibrillary tangles,central insuline resistance

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