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      GSK-3β, a pivotal kinase in Alzheimer disease

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          Abstract

          Alzheimer disease (AD) is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.

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          Most cited references142

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          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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            Alzheimer's disease.

            Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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              Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus.

              Adult neurogenesis in the dentate gyrus may contribute to hippocampus-dependent functions, yet little is known about when and how newborn neurons are functional because of limited information about the time course of their connectivity. By using retrovirus-mediated gene transduction, we followed the dendritic and axonal growth of adult-born neurons in the mouse dentate gyrus and identified distinct morphological stages that may indicate different levels of connectivity. Axonal projections of newborn neurons reach the CA3 area 10-11 d after viral infection, 5-6 d before the first spines are formed. Quantitative analyses show that the peak of spine growth occurs during the first 3-4 weeks, but further structural modifications of newborn neurons take place for months. Moreover, the morphological maturation is differentially affected by age and experience, as shown by comparisons between adult and postnatal brains and between housing conditions. Our study reveals the key morphological transitions of newborn granule neurons during their course of maturation.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                21 May 2014
                2014
                : 7
                : 46
                Affiliations
                [1] 1Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid Madrid, Spain
                [2] 2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III Madrid, Spain
                [3] 3Biology Faculty, Autónoma University Madrid, Spain
                Author notes

                Edited by: Akihiko Takashima, RIKEN Brain Science Institute, Japan

                Reviewed by: Luc Buee, Institut National de la Santé et de la Recherche Médicale, France; Hansen Wang, University of Toronto, Canada

                *Correspondence: Jesús ávila and María Llorens-Martín, Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, C/Nicolás Cabrera 1, 28049 Madrid, Spain e-mail: javila@ 123456cbm.uam.es ; mllorens@ 123456cbm.uam.es

                This article was submitted to the journal Frontiers in Molecular Neuroscience.

                Article
                10.3389/fnmol.2014.00046
                4033045
                24904272
                41aa240e-6512-4f79-be17-761e77a1ef3e
                Copyright © 2014 Llorens-Martín, Jurado, Hernández and Ávila.

                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) or licensor 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
                : 10 February 2014
                : 02 May 2014
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 169, Pages: 11, Words: 0
                Categories
                Neuroscience
                Review Article

                Neurosciences
                gsk-3β,alzheimer disease,kinase,neurodegeneration,tau proteins
                Neurosciences
                gsk-3β, alzheimer disease, kinase, neurodegeneration, tau proteins

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