Focus on the Locus: Elucidating the roles of tau pathology and the locus coeruleus in Alzheimer's Disease Open Access

Abstract

Alzheimer's disease (AD) is an insidious, progressive neurodegenerative disorder with societal and financial burdens that are escalating every single day. Despite knowing about the disease for over a century now, we are still unable to slow, stop or prevent it. The lack of a clear understanding of the underlying neuropathological mechanisms that govern the production and interaction of the two main pathologies of the disease: extracellular beta-amyloid plaques and intracellular tau neurofibrillary tangles, greatly hampers our ability to develop effective diagnostics and therapeutics. It has been particularly difficult to catch the disease at its earliest stages prior to irreversible neurodegeneration and cognitive damage as the neuropathological changes occur decades prior to outward clinical onset. Recently, it was discovered that an early form of tau pathology, a hyperphosphorylated tau precursor to the neurofibrillary tangles that fill AD brains, can be detected in the subcortical region of the brain in relatively young, cognitively unimpaired individuals. This early tau pathology is detected in the locus coeruleus (LC), the main source of norepinephrine to the brain, prior to anywhere else and before any other AD-like pathology such as beta-amyloid deposits. These findings fomented more research into the role of the LC in AD as an area with the potential to act as a "ground zero" for AD tau pathology. We have demonstrated here that this early presence of hyperphosphorylated tau in LC neurons is detrimental to their structure, significantly reducing their neurite lengths, as well as sensitizing them to secondary insults. Degeneration of the LC is also an established hallmark of AD and has been shown to exacerbate beta-amyloid pathologies and related cognitive impairments, and we are the first to show that it interacts in a similar manner with tau. Together, these studies have characterized the intertwining roles of tau and the LC at both the early stages where pretangle tau deposition can negatively impact the LC as well as later stages where LC degeneration in turn exacerbates tau pathology. In light of this evidence, it is clear that LC and the noradrenergic system are important targets within the pathogenesis of AD and could provide a wealth of information to improve the development of novel diagnostics and therapeutics to treat and prevent AD.

Table of Contents

TABLE OF CONTENTS

CHAPTER 1: BACKGROUND AND LITERATURE REVIEW............................. 1

1.1. Alzheimer's Disease...................................................................................... 2

1.1.1. Brief History of Alzheimer's Disease...................................................... 2

Discovery.................................................................................... 2

Epidemiology.............................................................................. 2

1.1.2. Clinical Presentation of the Disease........................................................ 4

Cognition..................................................................................... 4

Affect.......................................................................................... 5

Clinical Diagnosis........................................................................ 5

1.1.3. Neuropathology..................................................................................... 6

Beta-amyloid............................................................................... 6

Tau............................................................................................. 9

Advancements in Diagnostics Based on Neuropathology.............. 13

1.2. Locus coeruleus and the Norepinephrine System .......................................... 16

1.2.1. Basic characteristics............................................................................ 16

Anatomical Locus........................................................................ 16

Synthesis and Metabolism of Norepinephrine ............................... 17

Receptors and Signaling Pathways................................................ 18

Function...................................................................................... 19

1.2.2. Degeneration and Dysfunction in Alzheimer's Disease.......................... 19

Locus Coeruleus Loss in Alzheimer's........................................... 19

Preclinical Studies....................................................................... 20

Neuroinflammation as a Key Linking Mechanism.......................... 22

Increasing NE Ameliorates Pathology and Cognitive Decline

in Mice....................................................................................... 25

1.3. Interaction between Tau and the Locus Coeruleus in Alzheimer's Disease...... 28

1.3.1. Potential roles in Alzheimer's Pathogenesis.......................................... 28

Early Deposition of Subcortical Tau Pathology.............................. 29

Capacity of Locus Coeruleus Degeneration to ..................................

Aggravate Later Stage Tau Pathology ................................... 29

1.3.2. Knowledge Gaps................................................................................. 30

1.3.3. Modeling Tau and Locus Coeruleus Dysfunction.................................. 30

The P301S Mouse....................................................................... 31

N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4)................. 33

1.3.4. Thesis Aims........................................................................................ 35

CHAPTER 2: ABERRANT TAU IN THE LOCUS COERULEUS IMPACTS NEURITE LENGTH AND NEURONAL SENSITIVITY TO TOXIN IN VITRO ................... 38

2.1 Abstract ...................................................................................................... 39

2.2 Introduction................................................................................................ 40

2.3 Materials and Methods.................................................................................. 42

2.4 Results......................................................................................................... 47

2.5 Discussion................................................................................................... 50

CHAPTER 3: DSP-4 LESIONS OF THE LOCUS COERULEUS EXACERBATE NEUROPATHOLOGY IN A MOUSE MODEL OF TAUOPATHY...................... 62

3.1 Abstract....................................................................................................... 63

3.2 Introduction................................................................................................. 64

3.3 Materials and Methods.................................................................................. 66

3.4 Results......................................................................................................... 69

3.5 Discussion................................................................................................... 74

CHAPTER 4: BEHAVIORAL CONSEQUENCES OF LOCUS COERULEUS DEGENERATION IN A MOUSE MODEL OF HYPERPHOSPHORYLATED TAU............................................................................................................................... 99

4.1 Abstract .................................................................................................... 100

4.2 Introduction............................................................................................... 101

4.3 Materials and Methods................................................................................ 102

4.4 Results....................................................................................................... 107

4.5 Discussion................................................................................................. 113

CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS........................... 131

5.1 Summary................................................................................................... 132

5.2 Future Directions........................................................................................ 136

5.3 Future of Diagnostics and Therapeutics........................................................ 137

5.4 Conclusion................................................................................................. 140

REFERENCES 141

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Biology, Neuroscience Biology, Molecular
Keyword	norepinephrine locus coeruleus tau Alzheimer's
Committee Chair / Thesis Advisor	Weinshenker, David, Emory University Levey, Allan I, Emory University
Committee Members	Tansey, Malu, Emory University Kukar, Thomas, Emory University Walker, Lary C, Emory University

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