Cen, Siying (Fall 2018)

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Amyloid has been connected with protein misfolding diseases from the beginning, yet no clear mechanism for neurodegenerative diseases is currently proposed. One proposal is that the gut microbiome plays a role in the formation of amyloid plaques in the human brain. To evaluate the hypothesis that lipopolysaccharides (LPS) from gram-negative bacteria’s membrane participates in the Alzheimer’s disease (AD) at the molecular level, I have tested a model for β-amyloid (Aβ) peptides associating with LPS from gram-negative bacteria membrane, specifically determining whether the lipid A from LPS co-assembles with Aβ (16-22), the nucleating core of Aβ, and its congeners. In the experiments, lipid A and Aβ (16-22) were co-assembled in both aqueous and organic solutions, and the resulting structures characterized with TEM and ATR-FTIR. A type of glycerophospholipid, phosphatidylinositol (PI), was employed as a more soluble and simplified lipid A to mimic the co-assembling of lipid A and Aβ (16-22). My experiments demonstrate a direct interaction between LPS and Aβ (16-22) and CD results support the ability of LPS to induce β-sheet formation in soluble amyloid peptides. In summary, my research supports a direct association between Aβ peptides and LPS, the main component of bacterial outer membrane, but further experiments are needed to reveal the mechanism of LPS-Aβ peptides interaction, which may help explain the etiology of Alzheimer’s disease and bacterial toxicity.

Table of Contents


Table of Contents


Abstract 4


List of Figures. 11

List of Tables. 13

Chapter 1. Background. 1

Bacteria and neurodegenerative diseases. 1

Alzheimer’s disease and the amyloid peptide self-assembly. 1

Lipid-amyloid interactions and antimicrobial property of amyloid. 2

Potential of constructing co-assemblies of amyloid with lipids. 4

References. 6

Chapter 2. Exploring the interaction between LPS and amyloid peptide. 10

Introduction. 10

Methods. 11

Peptide synthesis and purification. 11

Peptide Assembly. 12

LPS assembly and LPS-Aβ incubation. 12

Transmission Electron Microscopy (TEM) 13

Circular Dichroism spectroscopy: 13

Results. 14

Characterizing the interaction between Aβ(16-22) peptide and LPS. 14

Time-dependent interaction of Aβ(1-40) and LPS. 18

Conclusion. 19

References. 19

Chapter 3. Defining the structure of lipid A-amyloid assembly 20

Introduction. 20

Methods. 21

Lipid A assembly. 21

Results. 22

TEM images of Aβ(16-22)-lipid A co-assemblies 22

pH-dependent co-assembly process 25

ATR-FTIR measurement of lipid A-Aβ (16-22) co-assemblies 27

Conclusion. 28

References. 33

Chapter 4. Constructing other lipid-amyloid assembly. 34

Introduction. 34

Experiment 35

PI Incubation. 35

Results. 36

Aβ(16-22) and PI assembly process 36

Conclusion. 39

Reference. 39

Chapter 5. Conclusion and perspectives 40

Conclusion. 43

Perspectives. 28

Define the structure of lipid A/Aβ (16-22) assemblies 28


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