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PhD Thesis |
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Investigation of
synaptic plasticity as memory formation mechanism and pathological amyloid fibrillation caused by β-amyloids aggregation Full Text PDF |
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Abstract |
The principles of biochemical
kinetics and system engineering are applicable in explaining complex
phenomena in neuroscience. Amyloid fibrillation and bioelectrical signaling in
synapses have been our subjects of research due to their significance. The former is related to the pathology of
many neurodegenerative diseases and the later is regarded as the microscopic
mechanism of memory. Claimed to be the number one cause
of senile dementia, Alzheimer’s disease is one of the disorders that involve misfolding of amyloid protein
and formation of insoluble fibrils.
Although a variety of time dependent fibrillation data in vitro are available, few
mechanistic models have been developed.
To bridge this gap we used chemical engineering concepts from polymer
dynamics, particle mechanics and population balance models to develop a
mathematical formulation of amyloid growth
dynamics. A three-stage mechanism
consisting of natural protein misfolding,
nucleation, and fibril elongation phases was proposed to capture the features
of homogeneous fibrillation responses.
In addition, the proposed mechanism reflects the effect of each factor
on fibril formation kinetics such as protein types, initial concentration,
seeding, and agitation over a series of experimental conditions. While our cooperative laboratory provided
us with experimental findings, we guided them with experimental design based
on modeling work. It was through the
iterative process that the size of fibril nuclei and concentration profiles
of soluble proteins were elucidated.
The study also reveals further experiments for diagnosing the
evolution of amyloid coagulation and probing
desired properties of potential fibrillation inhibitors. The accumulation of amyloid fibrils is suspected to cause abnormal
modification of long-term synaptic plasticity which is viewed as the
principal mechanism underlying learning and memory. Most synapses show long-term potentiation (LTP) or depression (LTD) which can last for
more than hours after tetanus stimuli are applied and removed. Even though there are hypotheses explaining
individual experimental findings, few systematic models have been built to
specify the actual mechanism contributing to long lasting change. Therefore, we first considered vesicle
trafficking in presynapse to describe the release
of glutamate as neurotransmitter. Then
in the postsynaptic compartment, we developed a calcium entrapment model to
simulate the excitatory current and voltage.
The systematic model consists of equivalent electrical circuits as
well as ligand- and voltage-gated NMDA
receptors. This built model is
supported by a broad range of experimental measurements. Thesis supervisor: Gregory J. McRae |
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Acknowledgement PDF |
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Chapter 1 |
Introduction PDF |
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Chapter 2 |
Methodology of Model Development PDF |
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Chapter 3 |
Modeling Amyloid
Fibrillation PDF |
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Chapter 4 |
Modeling Short-Term Plasticity PDF |
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Chapter 5 |
Modeling Long-Term Plasticity PDF |
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Chapter 6 |
Modeling Spike Timing Dependent Plasticity PDF |
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Chapter 7 |
Calcium Signaling and Amyloid
Fibril PDF |
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Chapter 8 |
Future Work PDF |
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Chapter 9 |
Conclusion PDF |
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Appendix A |
Supplemental Materials for Fibrillation Model PDF |
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Appendix B |
Supplemental Materials for STDP PDF |
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Appendix C |
Hodgkin-Huxley Equations PDF |
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Appendix D |
Artificial Neural Network PDF |
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