A Multi-Omic Approach to Define Molecular Changes in Human Tauopathy Restricted; Files Only

Abstract

Tauopathies are a heterogeneous class of disorders united in their common pathology: the deleterious accumulation of tau protein. As a major underlying cause of dementia, tauopathies pose a global health threat and research is urgently required to identify new therapeutic solutions. With this dissertation, I aimed to define how tauopathy impacts the human brain on a molecular level.

I begin by describing the biology of tau and summarizing the characteristic pathology, genetics, and clinical presentations of major tauopathies. I describe potential opportunities and challenges for targeting tau therapeutically and summarize important transcriptomic and proteomic studies of tauopathy, including prior work from our laboratory. I then use quantitative proteomics to identify the impact of tauopathy on the human grey and white matter proteome. I find that much of the grey and white matter proteome is shared, but they exhibit distinct expression profiles. Using a consensus weighted gene correlation network analysis (WGCNA), I identify unique and shared disease-associated changes in microglia and endothelia across grey and white matter. I then create a WGCNA network out of white:grey protein ratios and find a disease associated increase in mitochondrial proteins in white matter and decrease in grey matter. Next, I use a targeted transcriptomic approach to profile glial transcripts in human Alzheimer’s disease (AD) and frontotemporal dementia with tau pathology (FTD-tau). I find that glial related pathway scores including astrocytes, microglia, and oligodendrocytes are increased in FTD-tau. Finally, I discuss the advantages of systems biology approaches to defining molecular changes in human neurodegeneration and conclude that the results of this dissertation collectively demonstrated the importance of characterizing grey/white matter and glial changes in tauopathy.

Table of Contents

CHAPTER 1: AN OVERVIEW OF TAUOPATHY.. 1

1.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGMENT OF REPRODUCTION.. 2

1.2 ABSTRACT. 2

1.3 PHYSIOLOGY AND PATHOPHYSIOLOGY OF TAU.. 2

1.4 SUBCLASSIFICATION OF HUMAN TAUOPATHIES. 4

1.4.1 Alzheimer’s Disease. 5

1.4.2 Frontotemporal Dementia. 9

1.4.3 Progressive Supranuclear Palsy. 11

1.4.4 Corticobasal Degeneration. 12

1.4.5 Chronic Traumatic Encephalopathy. 13

1.5 PROSPECTIVE THERAPEUTIC STRATEGIES FOR TARGETING TAU.. 15

1.6 MOLECULAR CHANGES IN TAUOPATHY.. 16

1.7 A NEED FOR INCLUDING WHITE MATTER IN STUDIES OF TAUOPATHIES. 19

1.8 OVERVIEW OF THE DISSERTATION.. 20

CHAPTER 2: CONSENSUS AND RATIO PROTEOMIC NETWORKS OF GREY AND WHITE MATTER REVEAL TISSUE-SPECIFIC CHANGES IN HUMAN TAUOPATHY.. 24

2.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGMENT OF REPRODUCTION.. 25

2.2 ABSTRACT. 25

2.3 INTRODUCTION.. 26

2.4 MATERIALS AND METHODS. 27

2.4.1 Collection of human postmortem brain. 27

2.4.2 Preparation of brain homogenates. 28

2.4.3 Tandem Mass Tag (TMT) Labeling. 28

2.4.4 High pH Fractionation. 29

2.4.5 Liquid Chromatography Tandem Mass Spectrometry. 30

2.4.6 Proteomic Data Analysis. 30

2.5 RESULTS. 34

2.5.1 Cell-type specific proteins are differentially expressed in GM and WM DLPFC proteomes. 34

2.5.2 Consensus WGCNA reveals unique disease-associated endothelial and microglial protein changes in WM. 37

2.5.3 WGCNA of WM:GM ratio reveals disease-associated alterations in mitochondrial proteins. 39

2.6 DISCUSSION.. 40

2.7 ACKNOWLEDGMENTS. 43

TABLES. 44

FIGURES. 46

SUPPLEMENTAL FIGURES. 53

SUPPLEMENTAL FILES. 61

CHAPTER 3: GLIAL PROFILING OF HUMAN TAUOPATHY BRAIN DEMONSTRATES ENRICHMENT OF ASTROCYTIC TRANSCRIPTS IN TAU-RELATED FRONTOTEMPORAL DEGENERATION.. 62

3.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGMENT OF REPRODUCTION.. 63

3.2 ABSTRACT. 63

3.3 INTRODUCTION.. 63

3.4 MATERIALS AND METHODS. 65

3.4.1 Collection of postmortem brain tissue. 65

3.4.2 RNA isolation and NanoString nCounter glial profiling panel 66

3.4.3 Analysis of glial profiling panel results and comparison with corresponding proteome. 66

3.4.4 Statistical analysis and visualization methods. 67

3.5 RESULTS. 68

3.5.1 Glia- and neuron-associated transcripts display opposite patterns of differential expression in FTD-tau relative to control. 68

3.5.2 Glia-associated, particularly astrocytic, pathway scores, are increased in FTD-tau samples relative to control. 69

3.5.2.1 Neuronal pathways. 69

3.5.2.2 Oligodendrocyte pathways. 70

3.5.2.3 Microglial pathways. 71

3.5.2.4 Astrocyte pathways. 71

3.5.3 Cell type analysis reveals enrichment of astrocytic transcripts in FTD-tau. 72

3.5.4 Comparison of proteomic and glial profiling panel results. 73

3.6 DISCUSSION.. 74

3.6.1 Comparison of glial profiling panel with proteomic data yields novel insights. 74

3.6.2 Robust differential expression of astrocytic and inflammatory genes in FTD-tau. 75

3.6.3 Glial pathways are increased in FTD-tau. 76

3.6.4 Limitations and future studies. 77

3.7 CONCLUSION.. 78

3.8 ACKNOWLEDGEMENTS. 78

3.9 DATA STATEMENT. 79

TABLES. 80

FIGURES. 81

CHAPTER 4: DISCUSSION AND FUTURE DIRECTIONS. 102

4.1 SUMMARY OF RESULTS. 103

4.2 SYSTEMS BIOLOGY APPROACHES REVEAL THE MOLECULAR PATHWAYS THROUGH THE FOREST OF THOUSANDS OF MOLECULAR TREES. 104

4.2.1 Astrocytic transcripts and proteins are increased in FTD-tau. 104

4.2.2 Microglial changes in tauopathy. 105

4.2.3 White:Grey protein ratios reveal disease-associated signature of neurodegeneration. 105

4.3 LIMITATIONS AND FUTURE DIRECTIONS. 106

4.4 TRANSLATIONAL POTENTIAL. 109

4.5 CONCLUSION.. 109

REFERENCES 111

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Keyword	Frontotemporal dementia Tauopathy Proteomics Tau Astrocytes
Committee Chair / Thesis Advisor	Hales, Chadwick, Emory University
Committee Members	Zheng, James, Emory University Betarbet, Ranjita, Emory University Kukar, Thomas, Emory University Sloan, Steven, Emory University

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