Journal article
Insulin Inhibits A beta 42 Aggregation and Prevents A beta 42-Induced Membrane Disruption
Biochemistry (Easton), v 58(45), pp 4519-4529
12 Nov 2019
PMID: 31642314
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer's disease (AD) is associated with self-assembly of amyloid beta-protein (A beta) into soluble oligomers. Of the two predominant Afi 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, the extent to which insulin affects A beta dynamics and activity is unclear. 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 co-incubated 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 we propose to originate in misfolded insulin monomers. These hypothetically toxic misfolded monomers might contribute to the development of insulin resistance in early stages of T2D that are associated with abnormally high insulin levels. We show that in contrast to quiescent incubation, insulin incubated under 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.
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Details
- Title
- Insulin Inhibits A beta 42 Aggregation and Prevents A beta 42-Induced Membrane Disruption
- Creators
- Kaho Long - Drexel UniversityThomas L. Williams - Elsevier, Philadelphia, PA 19103 USABrigita Urbanc - Drexel University
- Publication Details
- Biochemistry (Easton), v 58(45), pp 4519-4529
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 11
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000497262600006
- Scopus ID
- 2-s2.0-85074724571
- Other Identifier
- 991019168143304721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology