Date of Award

5-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physics and Astronomy

Committee Member

Feng Ding, Committee Chair

Committee Member

Emil Alexov

Committee Member

Jian He

Committee Member

Hugo Sanabria

Abstract

Human islet amyloid polypeptide (IAPP, a.k.a. amylin) is a 37-residue peptide hormone co-synthesized and co-secreted with insulin by pancreatic β-cells for glycemic control. Extensive research indicates that the amyloid aggregation of IAPP into cross-β amyloid fibrils is a ubiquitous phenomenon as well as a major factor in the development and pathogenesis of type 2 diabetes mellitus (T2D), which is a long-term metabolic disorder compromises the quality of life of millions globally. The amyloid IAPP aggregation products, either soluble intermediate oligomers or mature fibrils, are found toxic to human cells and capable of eliciting systemic damage in T2D patients. Recent studies reveal that IAPP is able to cross the blood-brain barrier and co-aggregate with human amyloid-beta (Aβ), which is the protein associated with another amyloid neurodegenerative disorder, the Alzheimer’s disease (AD). In vitro experiments demonstrate that soluble IAPP could significantly accelerate the aggregation of Aβ, with accumulating clinical and epidemiological evidences also suggest that T2D and AD are linked together. Despite the significant differences in their pathologies, T2D is suggested as a risk factor for AD. Here, we investigate the possible mechanism of the co-aggregation of IAPP and Aβ to explore the cross-talk between these two diseases and propose that IAPP promotes Aβ aggregation by reducing the aggregation free energy barrier through its binding with Aβ. In addition, with the fact that IAPPs are stored inside β-cell granules without apparent aggregation in healthy individuals, we also study the physiological environment inside β-cell granules and its endogenous inhibition effect on IAPP aggregation. Our work demonstrates that Zn2+ coordinated molecular complex might be important to stabilize IAPP and hence the endogenous inhibition. Moreover, we study the interactions between IAPP and two different materials, the small molecule epigallocatechin gallate (EGCG) and the star-shaped polymer poly(2-hydroxyethyl acrylate) (PHEA). Our study demonstrates both EGCG and PHEA as inhibitors against amyloidogenesis, while perform in different strategies. EGCG is able to inhibit IAPP aggregation and result in minimizing the population of toxic oligomers and protofibrils, while PHEA accelerates IAPP fibrillation to circumvent accumulation of the more toxic intermediates.

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