Characterization of the Relationship Between LR11 and Tau Pathology Open Access

Sylvester, Ahmad Rashad (2014)

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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

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