Noradrenergic dysfunction in neurodegenerative disease Restricted; Files Only
Iannitelli, Alexa (Spring 2023)
Abstract
Neurodegenerative disease impacts millions of individuals worldwide, with incidence rates climbing alongside the average human lifespan. There are currently no therapeutic treatments for neurodegeneration, and as such, this process poses a public health risk. The two most common neurodegenerative disorders are Alzheimer’s and Parkinson’s diseases. Both diseases are pathologically characterized by the presence of abnormal protein aggregates, which lead to eventual dysfunction and degeneration of important neural systems. Interestingly, early pathology of both disorders can be found in a brainstem region called the locus coeruleus prior to most other areas of the brain. The locus coeruleus is responsible for central neurotransmission of the neuromodulator norepinephrine, and as such, it is responsible for a wide range of behaviors. As these neurons accumulate pathology, they become dysfunctional, leading to prodromal aspects of both Alzheimer’s and Parkinson’s diseases. These symptoms most often include sleep disturbances, anxiety, and cognitive decline, and are reported by patients to be among the most troublesome aspects of their disorders. Thus, there is an urgent need for the development of novel treatments for Alzheimer’s and Parkinson’s diseases. The work presented here assess two rodent models of locus coeruleus dysfunction and degeneration. The first, a selective neurotoxin, ablates axon terminals but spares cell bodies, providing a model of the very early noradrenergic dysfunction that precedes outright degeneration. Mice administered DSP-4 recapitulate phenotypes of neurodegenerative disease, including decreased catecholamine levels, increased inflammation, and novelty-induced anxiety-like behavior. These changes are coupled with a downregulation of important noradrenergic genes, indicating severe cellular harm. To further investigate the impact of noradrenergic dysfunction in a mouse model of neurodegeneration, we adapted an approach for driving pigmentation in the locus coeruleus. We found that pigmentation led to neurodegeneration as early as 1-week post-infusion, coupled with a depletion of catecholamines throughout the brain and increased anxiety-like behavior. On a molecular level, the presence of pigment granules leads to the upregulation of several pathways involved in apoptosis and other stress responses. By 6-weeks, the presence of this pigment in locus coeruleus neurons nearly completely degenerates the region, leaving a robust astrocyte response in its wake. Taken together, these models allow for a comprehensive assessment of noradrenergic dysfunction throughout neurodegeneration, both early on when only fibers are damaged, and also later, when degeneration begins to impact the cell bodies. These insights will inform future research into the precise mechanisms driving locus coeruleus dysfunction and degeneration in Alzheimer’s and Parkinson’s diseases.
Table of Contents
CHAPTER 1: INTRODUCTION……………………………………………………………… 1
1.1 THE LOCUS COERULEUS………………………………………………...………. 2
1.1.1 Composition………………………………………...…………………..... 2
1.1.2 Norepinephrine synthesis…………………………...…………………..... 2
1.1.3 Locus coeruleus function…………………………...…………………..... 4
1.2 ALZHEIMER’S DISEASE………………………………………………...………... 6
1.2.1 Epidemiology and etiology…………………………...…….…………..... 6
1.2.2 Clinical presentation…………………………...……………………........ 7
1.2.3 Neuropathology…………………………...…………...…………............. 9
1.2.4 The role of the locus coeruleus…………………………...…………….. 12
1.2.5 Rodent models…………………………….………...…….…………..... 13
1.3 PARKINSON’S DISEASE………………………………………………...……….. 15
1.3.1 Epidemiology and etiology……………………..…...…….…………..... 15
1.3.2 Clinical presentation…………………………...……………..……........ 18
1.3.3 Pathology…………………………...…………...……...………............. 21
1.3.4 The role of the locus coeruleus…………………………...…………….. 21
1.3.5 Animal models…………………………….………...…….…………..... 23
1.4 LOCUS COERULEUS SUSCEPTIBILITY………………………………...……... 26
1.5 NEUROMELANIN……………………………………………………......………. 28
1.5.1 Characteristics of neuromelanin………………..……………...……….. 28
1.5.2 Neuromelanin formation…………………………...…………...………. 28
1.5.3 Neurotoxicity of neuromelanin………………….……………...………. 30
1.5.4 Previous work in the field……………………….……………...………. 32
1.6 DISSERTATION AIMS………………………………….………………...………. 34
CHAPTER 2: THE NEUROTXOIN DSP-4 DYSREGULATES THE LOCUS COERULEUS-NOREPINEPHRINE SYSTEM AND RECAPIULATES MOLECULAR AND BEHAVIORAL ASPECTS OF PRODROMAL NEURODEGENERATIVE DISEASE…………………………………………………………………………...………….. 36
2.1 ABSTRACT…………………………………………………….………...………. 37
2.2 INTRODUCTION……………………………...……………….………...……… 38
2.3 MATERIALS AND METHODS……………...……………….………...………. 40
2.4 RESULTS……………...……………….………...……………………………… 48
2.5 DISCUSSION………...……………….………...………………………………... 53
CHAPTER 3: CONSEQUENCES OF PIGMENTATION ON LOCUS COERULEUS SURVIVAL AND FUNCTIONING………………………………………………………….. 69
3.1 ABSTRACT…………………………………………………….………...………. 70
3.2 INTRODUCTION……………………………...………………………....……… 71
3.3 MATERIALS AND METHODS……………...……………….………...………. 74
3.4 RESULTS……………...……………….………...……………………………… 81
3.5 DISCUSSION………...……………….………...………………………………... 87
CHAPTER 4: DISCUSSION………………………………………………………………... 101
4.1 SUMMARY……………………………………………………...……...………. 102
4.2 CONCLUSIONS AND FUTURE DIRECTIONS…..…………………..……… 102
4.2.1 DSP-4………………………………………………………………….. 102
4.2.2 Neuromelanin………………………………………………………….. 105
4.3 CONCLUDING REMARKS…………………………………...…….....………. 110
REFERENCES…………………………………………………………………………….………………………………... 112
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