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Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Berson, Amit ; Knobloch, Marlen ; Hanan, Mor ; Diamant, Sophia ; Sharoni, Michal ; Schuppli, Daniel ; Geyer, Brian C. ; Ravid, Rivka ; Mor, Tsafrir S. ; Nitsch, Roger M. ; Soreq, Hermona

In: Brain, 2008, vol. 131, no. 1, p. 109-119

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    Titre
    • Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology
    Auteur
    • Berson, Amit. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Knobloch, Marlen. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Hanan, Mor. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Diamant, Sophia. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Sharoni, Michal. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Schuppli, Daniel. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Geyer, Brian C.. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Ravid, Rivka. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Mor, Tsafrir S.. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Nitsch, Roger M.. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    • Soreq, Hermona. The Eric Roland Center for Neurodegenerative Diseases, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel, Division of Psychiatric Research, University of Zurich, 8008 Zurich, Switzerland, School of Life Sciences, Biodesign Institute, 874501, Arizona State University, Tempe, AZ 85287-4501, USA and Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Brain, 2008, vol. 131, no. 1, p. 109-119. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:295634
    Summary
    Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events