Characterization of the Relationship Between LR11 and Tau Pathology Open Access

Sylvester, Ahmad Rashad (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/2801ph077?locale=en
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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

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