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«Submitted to the Department of Biology, Chemistry, and Pharmacy At the Freie Universität Berlin By Philipp Jäger From Hamburg, Germany February ...»

-- [ Page 1 ] --

The Role of Autophagy in

Alzheimer Disease - from Cellular

Mechanisms to Systems Proteomics

Dissertation

To obtain the academic degree

Doctor rerum naturalium (Dr. rer. nat.)

Submitted to the

Department of Biology, Chemistry, and Pharmacy

At the Freie Universität Berlin

By

Philipp Jäger

From Hamburg, Germany

February 2011

Ex annis asperis, nunc propero ad Astra [sic].

This thesis work was performed between July 2006 and January 2011 under the

supervision of Prof. Dr. Tony Wyss-Coray at Stanford University, Palo Alto, CA, USA.

1st reviewer: Prof. Dr. Tony Wyss-Coray 2nd reviewer: Prof. Dr. Gerd Multhaup Disputation on the 23rd of May 2011.

Publications and statement of contribution Publications and statement of contribution This thesis has been submitted as a cumulative dissertation (Promotionsordnung des Fachbereiches Biologie, Chemie, Pharmazie der Freien Universität Berlin vom 04.09.2007 inkl. Erg. vom 07.02.2008). It is based on the following journal articles, both published and in preparation.

Title Contribution Jaeger PA, Britschgi M, Rufibach K, Burkholder B, Johns H, Sun 70% CH, Pradhan S, Petersen R, Knopman DS, Boeve BF, Boxer AL, Karydas A, Miller BL, Rademakers R, Dickson DW, Yonnkin S, Graff-Radford N, Wyss-Coray T. Plasma Protein Changes in Sporadic Alzheimer Disease Patients are Linked to Cognitive Decline and Identify Disease-related Pathways. (in preparation) Jaeger PA, Wyss-Coray T. Beclin 1 complex in autophagy and 100% Alzheimer disease. Arch Neurol. 2010 Oct;67(10):1181-4.

Jaeger PA, Pickford F, Sun CH, Lucin KM, Masliah E, Wyss-Coray 80% T. Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One. 2010 Jun 15;5(6):e11102.

Jaeger PA, Wyss-Coray T. All-you-can-eat: autophagy in 100% neurodegeneration and neuroprotection. Mol Neurodegener. 2009 Apr 6;4:16.

I confirm that the above stated author contributions are correct and that all my research has been conducted independently, following the ethical and practical standards of good scientific practice.

Philipp Jäger Palo Alto, the 25th of February 2011 Presentations Talks and poster presentations The author has presented the content of this research thesis at the following conferences.

Talks:

PA. Jaeger, M. Britschgi, CH. Sun, H. Johns, S. Pradhan, RC. Petersen, DS. Knopman, BF. Boeve, AL. Boxer, A. Karydas, BL. Miller, R. Rademakers, DW. Dickson, N.

Graff-Radford, T. Wyss-Coray: TheCommunicome of a Disease: Application and Potential of Human Plasma Proteomics to Study Frontotemporal Dementia. 40th Annual Meeting of the Society for Neuroscience 2010, San Diego/CA, USA, Nov 13-17, 2010.

PA. Jaeger, M. Britschgi, H. Johns, CH. Sun, T. Wyss-Coray: Exploring the Communicome of Frontotemporal Dementia Patients through Plasma Proteomics.

Consortium for Frontotemporal Dementia Research (CFR): Research in Progress Meeting, The J. David Gladstone Institute, San Francisco/CA, USA, Jun 4, 2010.

PA. Jaeger, F. Pickford, CH. Sun, KM. Lucin, T. Wyss-Coray: Beclin 1 Regulates APP Turnover in the Endosomal-lysosomal Pathway. Cold Spring Harbor Meeting "Neurodegenerative Diseases", Cold Spring Harbor Laboratory, Cold Spring Harbor/NY, USA, Dec 4-7, 2008.

F. Pickford, PA. Jaeger, E. Masliah, T. Wyss-Coray: Amyloid Precursor Protein Processing, Autophagy, and Alzheimer’s Disease. Herbsttagung der Gesellschaft für Biochemie und Molekularbiologie (GBM), Hamburg, Germany, Sep 16-19, 2007.

Presentations

Poster presentations:

PA. Jaeger, M. Britschgi, CH. Sun, S. Pradhan, H. Johns, T. Wyss-Coray: The Plasma Proteome of Secreted Cellular Communication Factors as a Tool to Study Dementia.

Keystone Symposium "Alzheimer's Disease Beyond Abeta", Copper Mt, CO, Jan 10-15, 2010.

PA. Jaeger, F. Pickford, CH. Sun, KM. Lucin, AR. LaSpada, T. Wyss-Coray: Beclin 1 Reduction Causes Accumulation of APP and APP Metabolites in Cells. Alzheimer’s Association Research Symposium, San Francisco/CA, USA, Jun 25, 2008.

F. Pickford, PA. Jaeger, E. Masliah, CH. Sun, M. Britschgi, S. Small, B. Spencer, E.

Rockenstein, N. Mizushima, B. Levine, T. Wyss-Coray: Effects of Autophagy on the Distribution and Processing of APP. 37th Annual Meeting of the Society for Neuroscience, San Diego/CA, USA, Nov 3-7, 2007.

F. Pickford, PA. Jaeger, E. Masliah, CH. Sun, M. Britschgi, S. Small, E. Rockenstein, N. Mizushima, B. Levine, T. Wyss-Coray: Beclin 1 Deficiency in Alzheimer's Disease Links Autophagy with Amyloidosis and Neurodegeneration. Keystone Symposium “Autophagy in Health and Disease”, Monterey/CA, USA, Apr 15-20, 2007.

Acknowledgements Acknowledgements This thesis is the cumulative work of many special people, united by the quest for scientific knowledge and medical improvements. First and foremost I would like to thank the patients and their families for allowing us to use their tissue samples for our research.

None of this would have been possible without their generosity and commitment.

Similarly important are our various funding sources, such as the National Institute of Health, the Department of Veterans Affairs, the John Douglas French Foundation, the Alzheimer Association, and the Consortium for Fronto-temporal Dementia Research.





I would also like to especially thank the Department of Biology, Chemistry, and Pharmacy at the Freie Universität Berlin, and specifically Prof. Dr. Gerd Multhaup, for showing a great deal of flexibility by supporting me to conduct my research on the other side of the world. The same is true for Stanford University, which has been an extraordinary place to work and study, and which has welcomed and nourished me with open arms. There, my special thanks go to the Graduate Program for the Neurosciences and the Stanford Institute for Neuro-Innovation & Translational Neurosciences, and their respective Directors and Administrators, past and present: Prof. Dr. William Newsome, Prof. Dr. John Huguenard, and Ross Colvin. They allowed me to participate in all program activities, both scientific and social, and made me immediately feel at home.

The laboratory of Prof. Dr. Tony Wyss-Coray has been a wonderful and extremely stimulating place to work, study, and develop a strong sense for the ways of scientific research. Many laboratory members have contributed to this work, both scientifically and spiritually, and I will not be able to name them all here. I would like to thank Dr. Fiona Pickford for helping me getting started in the laboratory as the first (!) graduate student, Dr. Markus Britschgi for sharpening my senses for details and precision, priceless when working with high-throughput data, and Dr. Hudson Johns, who helped me with countless hours of array scans and antibody and sample management.

Above all, I would like to express my deepest gratitude to Tony, not only for accepting me into his laboratory and generously funding my five years of research, but also for his fantastic and continuous support as a mentor, counselor, guide, colleague, and friend.

Acknowledgements

A vast amount of support came from my parents, Ruthild and Dr. Eckhard Jäger, who never rebelled against or vetoed my expatriate ambitions, always supported me with their unconditional love, and provided occasional (but highly appreciated) financial infusions. They joyfully embraced even my decision to marry an American woman, knowingly committing to many more years of long distance family reunions. They raised me to be who I am today, always encouraging my ventures to leave and see the world and to accept the foreign and strange not as an obstacle, but as a gem to be discovered. I promise to work hard to help them never feel the geographic distance!

Finally, my biggest Thank You of all goes to my charming and beautiful wife, Dr.

Lora Beatrice Jäger Sweeney. She supported me with all her energy throughout the last four years, supplied me with endless joy and happiness, challenged me with stimulating scientific discussions, and introduced me to the magic world of fly genetics and neurodevelopment. She is just the perfect mixture of a friendly competitor and a welcome detractor, always both pushing me to do my best at the bench and at the same time requesting my presence at terrible events such as skiing the Sierra Nevada Mountains, sailing the Pacific Ocean, hiking the Yellowstone National Park, or planting acres of tomato seedlings. And now she is the mother of our daughter. Nothing could be without her.

–  –  –

Table of contents Table of contents Publications and statement of contribution

Talks and poster presentations

Acknowledgements

Table of contents

List of figures

List of tables

Zusammenfassung (German)

Summary

Thesis Introduction

Alzheimer Disease

Mechanism of autophagy

Beclin 1 in autophagy

Autophagy in neurodegenerative disease

Beclin 1 and autophagy in Alzheimer Disease

Significance

References for thesis introduction

Chapter 1: Autophagy in Neurodegeneration and Neuroprotection

Summary

Background

Types of neuronal autophagy

Autophagy in the healthy nervous system

Autophagy as a clearing mechanism for protein degradation

Autophagy in vesicle sorting and organelle turnover

Autophagosomes as transport vacuoles

Regulation of autophagy

Autophagy in CNS disease and injury

Autophagy in chronic CNS diseases

Autophagy in acute CNS diseases and injuries

Autophagy and apoptosis

Table of contents

Concluding remarks

Abbreviations

Chapter 2: Regulation of Amyloid Precursor Protein Processing by the Beclin 1 Complex

Summary

Background

Results

Activation of autophagy promotes APP, APP-CTF, and A! degradation

Becn1 knockdown increases APP, APP-like proteins, APP-CTFs, and A!..................76 Overexpression of APP does not change Becn1 or Pik3c3 protein levels

Reduction of Becn1 impairs degradation of autophagosomes and reduces Pik3c3 levels

Inhibition of autophagosome turnover leads to a reduction in Becn1 and Pik3c3 levels

Becn1 overexpression reduces APP immunoreactivity

AD brains have less BECN1 and PIK3C3 and more LC3

Discussion

Material and methods

Acknowledgements

Chapter 3: The Beclin 1 Complex in Autophagy and Alzheimer Disease................108 Summary

Background

Autophagy is a vesicular degradation pathway for cytosolic components..................109 The Beclin 1 Connection: Autophagy, Neurodegeneration, and Alzheimer’s............112 Clinical Relevance and Current Research

Chapter 4: Plasma Protein Changes in Sporadic Alzheimer Disease Patients are Linked to Cognitive Decline and Identify Disease-related Pathways

Summary

Background

Antibody microarrays can reliably measure relative protein levels in plasma............123

Table of contents

Secreted signaling protein levels in AD patients differ from non-demented control patients and from patients with non-AD dementia

Penalized linear regression modeling confirms and expands the pool of proteins-ofinterest

The connectivity between secreted signaling proteins increases significantly in AD patients

Meta-analysis of the different statistical modules to rank proteins-of-interest and correlation with an independent measure of cognitive decline

Protein-interaction, PubMed co-occurance, gene-ontology, miRNA target, and chromosome band analysis

TNF"-, TGF!-, and angiogenic signaling alterations in AD

Discussion

Material and methods

Thesis Discussion

Autophagy in Alzheimer Disease

Changes in systemic plasma factors and their effects on autophagy

Outlook

References for thesis discussion

References for Chapters 1 to 4

Appendix:

Curriculum Vitae

Original Publications

List of figures List of figures Figure 1: APP trafficking and A! production

Figure 2: APP processing

Figure 3: Vesicle trafficking in autophagy

Figure 4: Beclin 1 deficiency in AD and APP transgenic mice

Figure 5: General thesis hypothesis

Figure 6: Steps in macroautophagy and chaperone mediated autophagy

Figure 7: Autophagy pathway in mammals

Figure 8: Control of autophagy

Figure 9: Interactions between autophagy and apoptosis

Figure 10: Expression of Becn1 and Pik3c3 in the mouse brain

Figure 11: Activation of autophagy promotes APP, APP-CTF, and A! degradation.......74 Figure 12: Effects of Atg5 knockdown on APP

Figure 13: Becn1 knockdown increases APP, APP-like proteins, APP-CTFs, and A!....78 Figure 14: Quantification of B103/hAPP cells

Figure 15: APP accumulation in CHO/hAPP cells after Becn1 siRNA

Figure 16: Effects of "-secretase inhibitors on Becn1 shRNA

Figure 17: Overexpression of APP does not change Becn1 or Pik3c3 protein levels.......83 Figure 18: Reduction of Becn1 implairs degradation of autophagosomes and reduced Pik3c3 levels

Figure 19: Inhibition of autophagosomal turnover leads to a reduction in Becn1 and Pik3c3 levels

Figure 20: Pharmaceutical inhibition of autophagy in CHO/hAPP and B103/hAPP cells

Figure 21: Becn1 overexpression reduces APP immunoreactivity

Figure 22: Control experiments for Becn1 lentiviral overexpression

Figure 23: AD brains have less BECN1 and PIK3C3 and more LC3

Figure 24: Effects of BECN1 deficiency in AD

Figure 25: Autophagy in mammalian cells

Figure 26: The role of Beclin 1 in autophagy and Alzheimer Disease

List of figures

Figure 27: Experimental Design of the microarray production and analysis..................119 Figure 28: Antibody microarray performance

Figure 29: Plasma proteins with differential levels

Figure 30: Independent cohort confirmation

Figure 31: Plasma proteins with differential connectivity

Figure 32: Meta analysis of the plasma protein hits

Figure 33: Ingenuity Pathway Analysis and biological correlation analysis

Figure 34: Concept of the signaling factor array

List of tables List of tables Table 1: Presence of autophagy related gene expression in neuronal tissue



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