The Role of the Immune Response in an LSD1-Induced Tauopathy-Like Neurodegeneration Mouse Model Restricted; Files Only

Abstract

Lysine-specific histone demethylase 1A (LSD1/KDM1A) is an epigenetic regulator and transcriptional repressor that plays an important role in maintaining neuronal identity and function. Previous studies from our lab reported that LSD1 is mislocalized and sequestered by cytoplasmic pathological tau in brain tissues from Alzheimer’s disease (AD) patients and in PS19 tauopathy mice. To study the consequence of LSD1 dysfunction, our lab generated inducible Lsd1 deletion mice (Lsd1^CAGG mice). Loss of LSD1 in adult mice induced severe neurodegeneration in brain regions vulnerable to AD and transcriptional alternations that significantly overlap with those observed in late-onset AD. These findings suggest that pathological tau might contribute to neurodegeneration by blocking the function of LSD1. To study the relationship between LSD1 and pathological tau, in chapter 2, we manipulated LSD1 levels in PS19 mice. Without altering tau pathology, we found that reducing LSD1 levels exacerbated disease phenotypes, whereas neuronal specific overexpression of LSD1 in the hippocampus rescued neurodegeneration. These findings indicate that LSD1 functions as a critical intermediate between pathological tau and downstream dysfunction. As a result, Lsd1^CAGG mice can be used as a model of late-stage AD. Because a strong immune response was observed in Lsd1^CAGG mice, in chapter 3 we investigated the role of microglia and TREM2-dependent microglial activation in this model. Our findings demonstrate that both microglial and microglia activation exert protective roles in Lsd1^CAGG mice. However, microglial depletion and inhibiting microglia activation via Trem2 deletion induced different effects on astrocyte reactivation and neuroinflammatory gene expression. These differences enabled us to conclude that microglia, rather than the broader immune response, are primarily responsible for the observed neuroprotective effect. In addition, we observe sex-dependent transcriptional effects when we ablate microglia in Lsd1^CAGG mice, highlighting the importance of considering biological sex when evaluating the function of the immune response in neurodegeneration. Recently, it has been suggested that inhibiting microglia activation may provide a therapeutic benefit for late-stage AD patients. Taken together, our results suggest that enhancing microglia activation, rather than blocking microglia activation, may be a better therapeutically strategy for late-stage AD. 

Table of Contents

Table of Contents

Chapter 1. Introduction

1.1 Alzheimer’s disease (AD) and neurodegeneration:

1.1.1 The epidemiology and burden of dementia and AD

1.1.2 The pathology of AD

1.1.3 The clinical features and comorbidities of AD

1.1.4 Disease progression and the importance of early intervention

1.1.5 The Etiology of AD

1.1.6 Amyloid hypothesis

1.1.7 Tau hypothesis

1.1.8 Neuroinflammation hypothesis

1.2 Alzheimer’s disease treatments:

1.2.1 Symptomatic therapies for cognitive symptoms:

1.2.1.1 Cholinesterase inhibitors:

1.2.1.2 Glutamate Regulators:

1.2.2 Symptomatic therapies for non-cognitive symptoms

1.2.3 Disease-modifying therapies targeting amyloid-β

1.2.3.1 anti-β-amyloid monoclonal antibodies:

1.2.3.2 The patient selection of anti-β-amyloid monoclonal antibodies:

1.2.3.3 The efficacy and clinical meaningfulness of anti-β-amyloid monoclonal antibodies:

1.2.3.4 Safety concerns and follow-up of anti-β-amyloid monoclonal antibodies:

1.2.3.5 The clinical issues of anti-β-amyloid monoclonal antibodies:

1.2.4 Disease-modifying therapies targeting tau

1.3 Neuroinflammation and microglia in neurodegeneration

1.3.1 Origin and development of microglia:

1.3.2 Physiological functions of microglia in the homeostasis:

1.3.3 Microglia in neurodegenerative disorders:

1.4 Transcriptional and epigenetic dysregulation in neurodegeneration

1.4.1 Tau-induced epigenetic dysregulation and loss of neuronal identity in AD

1.4.2 LSD1 and epigenetic regulation in neurodegeneration

Chapter 2: The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

2.1 Abstract

2.2 Significance statement

2.3 Introduction

2.4 Results

2.4.1 Tau pathology depletes LSD1 from the nucleus in the PS19 Tau mouse model

2.4.2 Reduction of LSD1 increases the mouse tauopathy phenotype

2.4.3 Reduction of LSD1 exacerbates PS19 Tau neurodegeneration

2.4.4 Tau pathology is not affected by change in LSD1 levels

2.4.5 The functional interaction between tau pathology and LSD1 inhibition is specific

2.4.6 Overexpression of LSD1 rescues neurodegeneration in the hippocampus of PS19 Tau mice

2.5 Discussion

2.6 Materials and methods

2.7 Acknowledgements

2.8 Figures

Chapter 3: Microglia and microglia activation are protective against LSD1-induced neurodegeneration

3.1 Introduction

3.2 Results

3.2.1 Loss of LSD1 induces microglia activation, astrocyte reactivity and a broader inflammatory response

3.2.2 Loss of LSD1 activates microglia morphologically

3.2.3 Loss of TREM2 attenuates the LSD1-induced immune response

3.2.4 Loss of TREM2 exacerbates disease progression in Lsd1^CAGG mice

3.2.5 Ablation of microglia does not block astrocyte reactivity or the broader inflammatory response induced by loss of LSD1

3.2.6 Ablation of microglia exacerbates disease progression in Lsd1^CAGG mice

3.2.7 The sex effects of PLX-induced microglial depletion

3.3 Discussion

3.4 Materials and Methods

3.5 Figures

Chapter 4: Discussion

4.1 LSD1 and related epigenetic mis-regulation as a potential target against Alzheimer’s disease

4. 2 Microglia as a potential therapeutic target against Alzheimer’s disease

4. 3 The roles of high fat diet (HFD) and Agmatine Sulfate in pathologies of Lsd1^CAGG mice

4.4 Limitations and future directions

Reference

 

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	TREM2 microglia epigenetics LSD1 (KDM1A) Alzheimer's disease tauopathy
Committee Chair / Thesis Advisor	Katz, David , Emory University
Committee Members	Levey, Allan , Emory University Weinshenker, David , Emory University Corces, Victor , Emory University Jiang, Jie , Emory University

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