Publication Date:
2015-09-01
Description:
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide. Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as eta-secretase activity. eta-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short Aeta peptides (termed Aeta-alpha and Aeta-beta). CTFs produced by eta-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and Aeta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aeta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aeta-alpha. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Willem, Michael -- Tahirovic, Sabina -- Busche, Marc Aurel -- Ovsepian, Saak V -- Chafai, Magda -- Kootar, Scherazad -- Hornburg, Daniel -- Evans, Lewis D B -- Moore, Steven -- Daria, Anna -- Hampel, Heike -- Muller, Veronika -- Giudici, Camilla -- Nuscher, Brigitte -- Wenninger-Weinzierl, Andrea -- Kremmer, Elisabeth -- Heneka, Michael T -- Thal, Dietmar R -- Giedraitis, Vilmantas -- Lannfelt, Lars -- Muller, Ulrike -- Livesey, Frederick J -- Meissner, Felix -- Herms, Jochen -- Konnerth, Arthur -- Marie, Helene -- Haass, Christian -- England -- Nature. 2015 Oct 15;526(7573):443-7. doi: 10.1038/nature14864. Epub 2015 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany. ; German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany. ; Department of Psychiatry and Psychotherapy, Technische Universitat Munchen, 81675 Munich, Germany. ; Institute of Neuroscience, Technische Universitat Munchen, 80802 Munich, Germany. ; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, 81377 Munich, Germany. ; Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Universite de Nice Sophia Antipolis, UMR 7275, 06560 Valbonne, France. ; Max Planck Institute of Biochemistry, Martinsried 82152, Germany. ; Gurdon Institute, Cambridge Stem Cell Institute &Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK. ; Institute of Molecular Immunology, German Research Center for Environmental Health, 81377 Munich, Germany. ; Department of Neurology, Clinical Neuroscience Unit, University of Bonn, 53127 Bonn, Germany. ; German Center for Neurodegenerative Diseases (DZNE) Bonn, 53175 Bonn, Germany. ; Institute of Pathology - Laboratory for Neuropathology, University of Ulm, 89081 Ulm, Germany. ; Department of Public Health/Geriatrics, Uppsala University, 751 85 Uppsala, Sweden. ; Institute for Pharmacy and Molecular Biotechnology IPMB, Functional Genomics, University of Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26322584" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
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Chemistry and Pharmacology
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Medicine
,
Natural Sciences in General
,
Physics
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