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Dissertation
The effect of insulin on self-assembly and toxicity of amyloid [beta]-protein: implications to type 2 diabetes and Alzheimer's disease
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2019
DOI:
https://doi.org/10.17918/7h5r-2v17
Abstract
Alzheimer's disease (AD) is associated with self-assembly of amyloid [beta]-protein (A[beta]) into soluble oligomers. Of the two predominant A[beta] alloforms, A[beta]40 and A[beta]42, the latter is particularly strongly linked to AD. Longitudinal studies revealed a correlation between AD and type 2 diabetes (T2D), characterized by abnormal insulin levels and insulin resistance. Although administration of intranasal insulin is explored as a therapy against AD, it is unclear to which extent insulin affects A[beta] dynamics and activity. We here investigate the effect of insulin on A[beta]42 self-assembly and characterize the capacity of insulin, A[beta]42, and A[beta]42 coincubated with insulin to disrupt the integrity of biomimetic lipid vesicles. We demonstrate that quiescently incubated insulin, which does not form amyloid fibrils, over time develops membrane-disrupting capacity which may be attributed to misfolded insulin monomers. These toxic insulin monomers might contribute to the development of insulin resistance in early stages of T2D, which are associated with abnormally high insulin levels. We show that in contrast to quiescent incubation, insulin incubated at agitated conditions readily forms amyloid fibrils, which protect against membrane permeation. Insulin quiescently incubated with A[beta]42 attenuates both A[beta]42 fibril formation and the ability of A[beta]42 to disrupt membranes in a concentration dependent manner. Our findings offer insights into interactions between insulin and A[beta]42 that are relevant to understanding the molecular basis of intranasal insulin as a therapy against A[beta]-induced AD pathology, thereby elucidating a plausible mechanism underlying the observed correlations between AD and T2D pathologies.
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Details
- Title
- The effect of insulin on self-assembly and toxicity of amyloid [beta]-protein
- Creators
- Kaho Long - DU
- Contributors
- Brigita Urbanc (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 135 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Arts and Sciences; Physics; Drexel University
- Other Identifier
- 11379; 991014632687004721