Characterization of the Relationship Between LR11 and Tau Pathology Open Access
Sylvester, Ahmad Rashad (2014)
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles (NFTs). Projected estimates of elderly population growth suggest that the already substantial societal and economic burdens imposed by AD will surge in coming years. Current treatments provide transient relief of select symptoms but fail to slow disease progression. Understanding the pathophysiology of AD may uncover pathological processes amenable to pharmacological manipulation, allowing interruption of disease progression. Recently, lower neuronal expression of LR11/SorLA was observed in cortex from cases with sporadic but not in familial AD (FAD). However, a subset of brains from individuals with mild cognitive impairment, a prodromal stage of AD, displayed reduced LR11/SorLA. Intronic polymorphisms in the LR11 gene, SORL1, correlated with increased risk of sporadic AD, suggesting altered protein expression but not function, confers increased risk of disease. In vitro and in vivo studies revealed an inverse relationship between LR11 expression and amyloid burden, presumably mediated by LR11 negatively regulating amyloidogenic processing of amyloid precursor protein via an intracellular sorting function. These data suggested that reduction of neuronal LR11 is an incipient event in AD that facilitates development of amyloid pathology. In this dissertation, I report a novel association between LR11 and NFTs in sporadic AD and FAD brain, with a preferential association between LR11 and early-stage NFTs. Differences in antibody use, disease severity, and brain region examined are shown to underlie the discrepancy between current and previous findings. I also demonstrate that LR11 associates with tau pathology in progressive supranuclear palsy (PSP) but not corticobasal degeneration (CBD) or Pick's disease (PiD) brain, indicating a preferential association with the 4 repeat straight filaments that characterize PSP. Evidence that 4 repeat aggregates and straight filaments are early forms of tau pathology is discussed and I propose two complimentary mechanisms by which LR11 may regulate development of tau pathology.
Table of Contents
General Introduction 1
Discovery 1
Current and Impending Societal Impact 3
Neuropathological Hallmarks of Alzheimer's Disease 4
Amyloid Plaques 4
Neurofibrillary Tangles 15
Genetic Risk Factors Associated with Development of AD 18
Down syndrome 18
Familial AD 19
Sporadic AD 21
LR11/SorLA 23
Discovery 23
The VPS10 Receptor Family 24
The Low-Density Receptor Family 25
Structure of LR11/SorLA 26
LR11/SorLA's Relationship to AD 28
Proposed Research 33
Materials and Methods 34
LR11 Antibodies 34
Tau Antibodies 36
Post-Mortem Human Brain Tissue 37
Human Embryonic Kidney (HEK) 293 Cells 39
Chromagen Immunohistochemistry (IHC) 39
Single-Chromagen IHC 39
Dual-Chromagen IHC 40
Modified Braak Staging Using LR11 CT-Positive Neurofibrillary Tangles 41
Dual-Fluorescence Immunohistochemistry 43
Western Blotting 43
Statistical Analyses 45
LR11 Associates with Early-Stage Neurofibrillary Tangles in Alzheimer's Disease 46
Introduction 46
Results 48
Identification of NFT-Like Structures with LR11 CT Antibody 48
LR11 CT Antibody Labeling of NFTs Confirmed 50
LR11 CT but Not LR11 3850 Labels NFTs in Sporadic AD 55
Case Selection and Regional Differences: LR11 CT-Positive NFTs and Braak Staging 55
Revisiting FAD (and DS): LR11 CT Antibody Labels NFTs in FAD and DS Brain 58
LR11 Preferentially Associates with Early-Stage NFTs 61
Discussion 64
LR11 Associates with Tau Pathology in Progressive Supranuclear Palsy but Not Corticobasal Degeneration or Pick's Disease 68
Introduction 68
Alzheimer's Disease (AD) 68
Progressive Supranuclear Palsy (PSP) 69
Corticobasal Degeneration (CBD) 70
Pick's Disease (PiD) 71
Results 73
LR11 CT Antibody Labels NFTs in PSP Brains 73
LR11 CT Antibody Does Not Label CBD Pathology 73
LR11 CT Labels Isolated Pick Bodies in PiD Brains 76
Discussion 76
General Discussion 80
LR11/SorLA 80
Tau Pathology 82
Summary and Interpretation of Results 85
LR11 in AD Brain 85
LR11 in Non-AD Tauopathies 89
Conclusion 96
References 99
About this Dissertation
School | |
---|---|
Department | |
Subfield / Discipline | |
Degree | |
Submission | |
Language |
|
Research Field | |
Keyword | |
Committee Chair / Thesis Advisor | |
Committee Members |
Primary PDF
Thumbnail | Title | Date Uploaded | Actions |
---|---|---|---|
Characterization of the Relationship Between LR11 and Tau Pathology () | 2018-08-28 14:29:29 -0400 |
|
Supplemental Files
Thumbnail | Title | Date Uploaded | Actions |
---|