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      Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits

      1 , 2 , 2 , 4 , 5 , 2 , 3 , 5 , 1 , 2 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

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          Most cited references 99

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          LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.

          Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.
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            TOR signaling in growth and metabolism.

            The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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              Alzheimer's disease.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                28 September 2011
                : 6
                : 9
                Affiliations
                [1 ]Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                [2 ]The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                [3 ]Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                [4 ]Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                [5 ]Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, Texas, United States of America
                Emory University, United States of America
                Author notes

                Conceived and designed the experiments: SO. Performed the experiments: SM. Analyzed the data: SO. Contributed reagents/materials/analysis tools: RS AR. Wrote the paper: SO.

                Article
                PONE-D-11-15340
                10.1371/journal.pone.0025416
                3182203
                21980451
                Majumder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Biochemistry
                Cytochemistry
                Organelles
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Cellular Structures
                Subcellular Organelles
                Neuroscience
                Molecular Neuroscience
                Signaling Pathways
                Neurobiology of Disease and Regeneration
                Medicine
                Neurology
                Dementia
                Alzheimer Disease

                Uncategorized

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