Research ArticleAging Open Access | 10.1172/JCI170550

Andree Schmidt,1,2,3,4 Brian Hrupka,5 Frauke van Bebber,1 Sanjay Sunil Kumar,6 Xiao Feng,1,2 Sarah K. Tschirner,1,2 Marlene Aßfalg,1,2 Stephan A. Müller,1,2 Laura Sophie Hilger,1,7,8 Laura I. Hofmann,1,2 Martina Pigoni,1,2,3 Georg Jocher,1,2 Iryna Voytyuk,9,10 Emily L. Self,11 Mana Ito,12 Kana Hyakkoku,12 Akimasa Yoshimura,12 Naotaka Horiguchi,12 Regina Feederle,1,13,14 Bart De Strooper,9,10,15 Stefan Schulte-Merker,6 Eckhard Lammert,7,16,17 Dieder Moechars,5 Bettina Schmid,1 and Stefan F. Lichtenthaler1,2,14

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

Find articles by Müller, S. in: JCI | PubMed | Google Scholar

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

Find articles by Self, E. in: JCI | PubMed | Google Scholar

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

Find articles by Ito, M. in: JCI | PubMed | Google Scholar

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

Find articles by Hyakkoku, K. in: JCI | PubMed | Google Scholar

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan F. Lichtenthaler, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany. Phone: 4989.4400.46425; Email: stefan.lichtenthaler@dzne.de.

Authorship note: Co–first authors AS and BH contributed equally to this work.

Find articles by Yoshimura, A. in: JCI | PubMed | Google Scholar

1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

2Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

3Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.

4Evotec München, Neuried, Germany.

5Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.

6Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.

7Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and

8International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.

9Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

10Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.

11MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

12Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.

13Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.

16Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

17German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Address correspondence to: Stefan