Cellular Trafficking and molecular heterogeneity of amyloid beta seeds. How similar are beta amyloid aggregates and prions? Open Access

Cintron, Amarallys Francesca (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/s4655h523?locale=en


As the deposition of aggregated beta-amyloid peptide in the brain parenchyma is an obligatory event in Alzheimer's disease, beta-amyloid has become the subject intensive study. In this thesis work, my primary aim has been to investigate key similarities between beta-amyloid seeds and prions, the proteinaceous agents that underlie spongiform encephalopathies. Research on prion diseases established the novel concept that certain proteins can cause disease by a process involving misfolding and aggregation. The prion paradigm has increasingly found parallels in more common neurodegenerative diseases. I have investigated several prion-like characteristics of beta-amyloid seeds, including seed durability, transport by immune cells, and the existence of structural/functional variants (strains). I found, like prions, beta-amyloid seeds are resistant to destruction by formaldehyde fixation. Specifically, fixation does not eliminate the ability of beta-amyloid seeds to induce the formation of plaques and cerebral beta-amyloid angiopathy in an APP transgenic mouse model of cerebral beta-amyloid deposition. Inflammation commonly occurs in numerous neurodegenerative diseases. In Alzheimer's disease, some studies show that macrophages are beneficial to plaque clearance, but others suggest that plaques contribute to the deposition of beta-amyloid. Here, I demonstrate that macrophages can phagocytose beta-amyloid seeds in the periphery and transport them across the blood brain barrier in mice. While this finding indicates that macrophages could contribute to seed spread, a preliminary investigation using beta-amyloid -rich brain extract yielded a small decrease in brain beta-amyloid in APP-transgenic mice seven months later. Lastly, I undertook an analysis of prion-like strain differences in beta-amyloid. The imaging compound Pittsburgh Compound B (PIB) binds with high specificity and affinity to beta-amyloid in human brains. By seeding APP-transgenic mice with beta-amyloid -rich brain extracts, I was able to induce the deposition of beta-amyloid, which stimulates PIB binding to the deposits at an early age. Because these PIB-positive deposits are induced in the mice by human, nonhuman primate and murine beta-amyloid seeds, it appears that seeding acts to accelerate lesion maturation, and that the beta-amyloid deposit's molecular conformation can evolve with age. Taken together, these experiments support the concept that beta-amyloid seeds share important structural and biological features with prions.

Table of Contents

Chapter 1 Introduction and Background. 1

1.1 A brief history of Alzheimer's disease. 2

1.2 Dementia and Alzheimer's disease. 3

1.3 The neuropathology of Alzheimer's disease. 5

1.4 Molecular mechanisms of protein aggregation: The prion paradigm. 9

1.5 Inflammation and AD. 12

1.6 Cellular mechanisms in AD. 15

1.7 Animal models of Alzheimer-type neuropathology. 16

1.8 Therapeutic approaches to AD. 17

Chapter 2 Beta-amyloid seeds resist inactivation by formaldehyde. 21

2.1 Abstract. 22

2.2 Introduction. 23

2.3 Materials and methods. 24

2.4 Results and Discussion. 28

Chapter 3 Transport of Aggregated Beta-amyloid and Other Cargo from Periphery to Brain by Circulating Monocytes. 41

3.1 Abstract. 42

3.2 Introduction. 43

3.5 Methods. 45

3.3 Results. 50

3.4 Discussion. 53

3.6 Long term effects of exogenous, Beta-amyloid seed-laden circulating monocytes on cerebral beta-amyloid deposition in APP-transgenic mice. 64

3.6.1 Methods. 64

3.6.2 Results. 65

3.6.3 Discussion. 66

Chapter 4 Seeding PIB-Positive beta-amyloid Plaques and Cerebral beta-amyloid Angiopathy in APP-Transgenic Mouse Models. 72

4.1 Abstract. 74

4.2 Introduction. 74

4.3 Materials and Methods. 75

4.4 Results. 78

4.5 Discussion. 79

Chapter 5 Discussion and Future Directions. 85

Similarity of Prions and beta-amyloid. 86

Inflammation and Alzheimer's disease. 90

Future Directions. 93

References. 95

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