Locus coeruleus physiology in physiology in Alzheimer’s disease Open Access

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and is expected to pose a significant societal and financial burden as the population ages. AD is characterized by the aggregation of extracellular amyloid-beta plaques and intracellular tau neurofibrillary tangles. Therapeutic interventions have targeted these two protein aggregates but have failed to yield a cure. Subcortical regions, and specifically the noradrenergic locus coeruleus (LC), are the earliest sites of tau aggregation, occurring decades prior to the onset of cognitive deficits. However, the consequences of such early tau pathology in the LC are not well defined. Specifically, changes in LC activity in AD are inferred by their correlates in human imaging and behaving animals, and the consequences of hyperphosphorylated tau on neuronal activity in other brain regions. In this dissertation, I first described how tau pathology affects LC activity with electrophysiological recordings in wild-type (WT) and TgF344-AD rats, a preclinical model of AD that develops LC tau pathology prior to substantial pathological forebrain deposition. I next explored mechanisms underlying this altered activity by comparing LC gene expression in age-matched WT and TgF344-AD animals. Finally, I expanded previous behavioral characterizations of this rat model by testing measures of anxiety-like phenotypes, arousal, and active/passive coping. I found LC hyperactivity and downregulation of inhibitory markers coincident with the emergence of anxiety-like behaviors in 6-month TgF344-AD rats. Meanwhile, 15-month TgF344-AD rats demonstrate LC hypoactivity and a compensatory upregulation of genes involved in norepinephrine synthesis, packaging, and reuptake in a likely attempt to counteract worsening cognitive deficits at this age. Overall, this dissertation confirms and extends previous models of LC dysfunction along the progression of AD. Namely, that early non-cognitive behavioral phenotypes are consistent and coincident with the appearance of LC hyperphosphorylated tau pathology and increased neuronal firing, while later LC hypoactivity parallels the emergence of disease-typical cognitive impairments. I add potential mechanistic underpinnings by delineating changes in LC molecular signatures that align with observed changes in LC activity and behavior at each stage. These data will be crucial for the rational design and implementation of noradrenergic-based therapies to improve AD symptoms and impede disease progression.

Table of Contents

CHAPTER 1: INTRODUCTION 1

1.1 THE LOCUS COERULEUS 2

1.1.1 COMPOSITION, STRUCTURE, AND ORGANIZATION 2

1.1.2 NOREPINEPHRINE SYNTHESIS, RELEASE, AND DEGRADATION 4

1.1.2.1 Norepinephrine Synthesis 4

1.1.2.2 Norepinephrine Release and Receptors 5

1.1.2.3 Norepinephrine Reuptake, Recycling, and Degradation 6

1.1.2.4 Neurotransmitter and neuropeptide co-release 6

1.1.3 LOCUS COERULEUS FIRING PATTERNS AND INFLUENCE ON BEHAVIOR 7

1.1.3.1 Firing Rates, Patterns, and Characteristics 7

1.1.3.2 Neurochemical Control of Locus Coeruleus Firing Patterns 9

1.1.3.3 Behavior 11

1.2 CONTRIBUTIONS OF LOCUS COERULEUS DYSFUNCTION TO DISEASE 20

1.2.1 NEUROPSYCHIATRIC AND NEURODEVELOPMENTAL DISORDERS 20

1.2.2 SLEEP DISORDERS 21

1.2.3 NEURODEGENERATIVE DISORDERS 22

1.3 ALZHEIMER’S DISEASE 23

1.3.1 EPIDEMIOLOGY AND ETIOLOGY 23

1.3.2 NEUROPATHOLOGY 26

1.3.2.1 Amyloid-β 26

1.3.2.2 Tau 27

1.3.3 CLINICAL PRESENTATION 29

1.3.3.1 Cognition and Memory 29

1.3.3.2 Prodromal Symptomology 29

1.3.4 CONTRIBUTIONS OF LOCUS COERULEUS DYSFUNCTION TO ALZHEIMER’S DISEASE 30

1.3.4.1 Susceptibility 30

1.3.4.2 Dysfunction 32

1.3.4.3 Current State of Noradrenergic Therapies in Alzheimer’s Disease 34

1.4 PRECLINICAL MODELS OF ALZHEIMER’S DISEASE 35

1.4.1 IN VITRO MODELS 35

1.4.2 MODELING ALZHEIMER’S DISEASE WITH PHARMACOLOGY 37

1.4.3 VIRAL VECTOR AND SEEDING MODELS 37

1.4.4 GENETIC MODELS 39

1.4.4 RAT MODELS WITH A FOCUS ON THE TGF344-AD RAT 40

1.4.4 NON-HUMAN PRIMATES 42

1.5 PREVIOUS WORK AND GAPS IN THE FIELD 43

1.6 DISSERTATION AIMS 44

CHAPTER 2: AGE-DEPENDENT DYSREGULATION OF LOCUS COERULEUS FIRING IN A TRANSGENIC RAT MODEL OF ALZHEIMER’S DISEASE 52

ABSTRACT 53

2.1 INTRODUCTION 54

2.2 METHODS 56

2.2.1 Animals 56

2.2.2 Surgery 56

2.2.3 Electrophysiology 57

2.2.4 Tissue Preparation and Immunohistochemistry 58

2.2.5 Statistical Analysis 59

2.3 RESULTS 59

2.3.1 LC Neural Recording Verification 60

1.3.2 Alteration of Pacemaker-like LC Firing in TgF344-AD Rats 60

1.3.3 Dysregulated LC Response to Footshock in TgF344-AD Rats 61

2.4 DISCUSSION 62

2.4.1 Overview of changes in LC firing and association with symptoms of AD 62

2.4.2 Potential mechanisms underlying changes in LC firing rates 64

2.4.3 Clinical Implications 66

2.4.4 Limitations 67

2.5 CONCLUSIONS 68

CHAPTER 3: DISRUPTED GENE EXPRESSION SIGNATURES OF LOCUS COERULEUS NEURONS IN A RAT MODEL OF ALZHEIMER’S DISEASE 77

ABSTRACT 78

3.1 INTRODUCTION 79

3.2 MATERIALS AND METHODS 82

3.2.1 Animals 82

3.2.2 Tissue Collection 82

3.2.3 In Situ Hybridization, Imaging, and Analysis 82

3.2.4 Statistical Analysis 83

3.3 RESULTS 83

3.4 DISCUSSION 87

3.5 CONCLUSIONS 95

CHAPTER 4: CONSEQUENCES OF HYPERPHOSPHORYLATED TAU IN THE LOCUS COERULEUS ON BEHAVIOR AND COGNITION IN A RAT MODEL OF ALZHEIMER’S DISEASE 107

ABSTRACT 108

4.1 INTRODUCTION 109

4.2 MATERIALS AND METHODS 112

4.2.1 Animals 112

4.2.2 Stereotaxic Injections 113

4.2.3 Behavioral Assays 113

4.2.3.1 General 113

4.2.3.2 Sleep latency 114

4.2.3.3 23-h locomotor activity 114

4.2.3.4 Open field 114

4.2.3.5 Elevated plus maze 115

4.2.3.6 Forced swim test 115

4.2.3.7 Morris water maze 115

4.2.3.8 Novelty-suppressed feeding 116

4.2.3.9 Fear conditioning 117

4.2.4 Tissue Preparation & Immunohistochemistry 118

4.2.5 Image Analysis 118

4.2.6 Statistics and Analysis 119

4.3 RESULTS 120

4.3.1 Confirmation of viral expression 120

4.3.2 General Arousal and Locomotion 120

4.3.2.1 Sleep Latency 120

4.3.2.2 23-h locomotion 121

4.3.3 Anxiety- and active/passive coping-like behavior 122

4.3.3.1 Open field 122

4.3.3.2 Elevated plus maze 122

4.3.3.3 Novelty-suppressed feeding 122

4.3.3.4 Forced swim test 123

4.3.4 Learning and Memory 123

4.3.4.1 Morris water maze 123

4.3.4.2 Fear conditioning 124

4.3.5 Hippocampus Pathology 125

4.3.6 Hippocampus NE Innervation 127

4.4 DISCUSSION 127

CHAPTER 5: DISCUSSION AND FUTURE DIRECTIONS 167

5.1 SUMMARY AND INTEGRATION OF KEY FINDINGS 168

5.2 CLINICAL IMPLICATIONS 172

5.3 FUTURE DIRECTIONS 178

5.4 FINAL REMARKS 182

REFERENCES 183

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 Health Sciences, Aging
Keyword	Locus coeruleus Alzheimer's disease Tau TgF344-AD Amyloid
Committee Chair / Thesis Advisor	Weinshenker, David, Emory University
Committee Members	Keilholz, Shella, Emory University Weiss, Jay, Emory University Singer, Annabelle, Emory University Vazey, Elena, University of Massachusetts Amherst

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