[en] While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.
Disciplines :
Neurology
Author, co-author :
Islam, Md Rezaul; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Kaurani, Lalit; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany ; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
Berulava, Tea; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Heilbronner, Urs; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Budde, Monika; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Centeno, Tonatiuh Pena ; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Elerdashvili, Vakthang; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Zafieriou, Maria-Patapia ; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany
Benito, Eva; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Sertel, Sinem M; Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany
Goldberg, Maria ; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Senner, Fanny; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany
Kalman, Janos L; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany
Burkhardt, Susanne; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Oepen, Anne Sophie; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Sakib, Mohammad Sadman; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Kerimoglu, Cemil ; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany
Wirths, Oliver ; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
Bickeböller, Heike; Department of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany
Bartels, Claudia; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
Brosseron, Frederic ; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Buerger, Katharina; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
Cosma, Nicoleta-Carmen ; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
Fliessbach, Klaus; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Janowitz, Daniel; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
Kilimann, Ingo; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
Kleinedam, Luca; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Laske, Christoph; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Metzger, Coraline D; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany ; Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany
Munk, Matthias H; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Perneczky, Robert ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany ; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany ; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK
Peters, Oliver; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany ; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Rauchmann, Boris S ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany
Roy, Nina; German Center for Neurodegenerative Diseases, Bonn, Germany
Schneider, Anja; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Spottke, Annika; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurology, University of Bonn, Bonn, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Teipel, Stefan; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
Tscheuschler, Maike; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany
Wagner, Michael; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Wiltfang, Jens ; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany ; Department of Medical Sciences, Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
Düzel, Emrah; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Köln, Germany
Delcode Study Group
Rizzoli, Silvio O ; Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany ; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
Zimmermann, Wolfram-Hubertus; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany ; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany ; DZKH (German Center for Cardiovascular Diseases), Göttingen, Germany
Schulze, Thomas G; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany
Falkai, Peter; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany
Sananbenesi, Farahnaz ; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, München, Germany ; German Center for Neurodegenerative Diseases, Research Group for Genome Dynamics in Brain Diseases, Göttingen, Germany
Fischer, Andre ; Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen, Germany ; Department for Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; German Center for Neurodegenerative Diseases, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany ; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
H2020 European Research Council Deutsche Forschungsgemeinschaft Bundesministerium für Bildung und Forschung Common Fund
Funding text :
The authors thank Dr. Guobin Bao, Dr. Stefan Irniger, Dr. Rashi Halder, Dr. Johannes Söding, Dr. Saikat Banerjee, Dr. Torsten Klengel, Dr. Carmelo Ferrai, and Dr. Dennis Krüger and Petra Tucholla for their technical supports and suggestions to the work. Generation of the GMP line LiPSC-GR1.1 was supported by the NIH Common Fund Regenerative Medicine Program and reported in Stem Cell Reports. The NIH Common Fund and the National Center for Advancing Translational Sciences (NCATS) are joint stewards of the LiPSC-GR1.1 resource. MRI and MSS are members the international Max Planck Research School (IMPRS) for Neuroscience, Göttingen, and JLK is a member of the IMPRS for Translational Psychiatry, Munich, Germany. T.G.S. was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the projects KFO241 (www.kfo241.de and www. PsyCourse.de) (SCHU 1603/4-1, 5-1, 7-1, FA241/16-1), by the German Federal Ministry of Education and Research (BMBF) projects IntegraMent (Integrated; (01ZX1614K) and BipoLife network (01EE1404H) and the Dr. Lisa Oehler Foundation, Kassel (Germany). This work was supported by the following third party funds to AF: DFG research group KFO241/PsyCourse Fi981-4 and Fi981 11-1, and DFG Project FI98176-2 and 15-1 related to the Priority program SPP1738, the ERC consolidator grant DEPICODE (648898), the BMBF projects ENERGI (01GQ1421A) and Intergament (01ZX1314D), the SFB1286, the DFG under Germany’s Excellence Strategy—EXC 2067/1 390729940 and funds from the German Center for Neurodegenerative Diseases FS was supported by the DFG grant SA1005/2-1 and funds from the DZNE. PF was supported by the KFO241/PsyCourse project FA 241/16-1.The authors thank Dr. Guobin Bao, Dr. Stefan Irniger, Dr. Rashi Halder, Dr. Johannes Söding, Dr. Saikat Banerjee, Dr. Torsten Klengel, Dr. Carmelo Ferrai, and Dr. Dennis Krüger and Petra Tucholla for their technical supports and suggestions to the work. Generation of the GMP line LiPSC‐GR1.1 was supported by the NIH Common Fund Regenerative Medicine Program and reported in Stem Cell Reports. The NIH Common Fund and the National Center for Advancing Translational Sciences (NCATS) are joint stewards of the LiPSC‐GR1.1 resource. MRI and MSS are members the international Max Planck Research School (IMPRS) for Neuroscience, Göttingen, and JLK is a member of the IMPRS for Translational Psychiatry, Munich, Germany. T.G.S. was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the projects KFO241 ( www.kfo241.de and www . PsyCourse.de ) (SCHU 1603/4‐1, 5‐1, 7‐1, FA241/16‐1), by the German Federal Ministry of Education and Research (BMBF) projects IntegraMent (Integrated; (01ZX1614K) and BipoLife network (01EE1404H) and the Dr. Lisa Oehler Foundation, Kassel (Germany). This work was supported by the following third party funds to AF: DFG research group KFO241/PsyCourse Fi981‐4 and Fi981 11‐1, and DFG Project FI98176‐2 and 15‐1 related to the Priority program SPP1738, the ERC consolidator grant DEPICODE (648898), the BMBF projects ENERGI (01GQ1421A) and Intergament (01ZX1314D), the SFB1286, the DFG under Germany’s Excellence Strategy—EXC 2067/1 390729940 and funds from the German Center for Neurodegenerative Diseases FS was supported by the DFG grant SA1005/2‐1 and funds from the DZNE. PF was supported by the KFO241/PsyCourse project FA 241/16‐1.
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