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      Mitochondria as a therapeutic target in Alzheimer's disease

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          Abstract

          Alzheimer's disease (AD) remains the most common neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition and memory loss. Studies have shown that mitochondrial dysfunction plays a crucial role in AD, which involves oxidative stress-induced respiratory chain dysfunction, loss of mitochondrial biogenesis, defects of mitochondrial dynamics and mtDNA mutations. Thus mitochondria might serve as drug therapy target for AD. In this article, we first briefly discussed mitochondrial theory in the development of AD, and then we summarized recent advances of mitochondrial abnormalities in AD pathology and introduced a series of drugs and techniques targeting mitochondria. We think that maintaining mitochondrial function may provide a new way of thinking in the treatment of AD.

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          Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization.

          Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.
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            The role of exercise and PGC1alpha in inflammation and chronic disease.

            Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.
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              SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.

              A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                16 June 2016
                September 2016
                16 June 2016
                : 3
                : 3
                : 220-227
                Affiliations
                [1]Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China
                Author notes
                []Corresponding author. woodchen2015@ 123456163.com
                Article
                S2352-3042(16)30023-X
                10.1016/j.gendis.2016.05.001
                6150105
                30258891
                8b3a01df-e51f-4356-89b4-7f9623a8feb6
                Copyright © 2016, Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 April 2016
                : 30 May 2016
                Categories
                Article

                alzheimer's disease,antioxidant,biogenesis,dynamics,mitochondria,mtdna,therapy

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