Related Experiment Video
Updated: Jun 1, 2026
15:04
Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity
Nicholas B Last1, Elizabeth Rhoades, Andrew D Miranker
1Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
Summary
Small oligomers of islet amyloid polypeptide form on cell membranes, disrupting them and causing cell death. This discovery reveals a new pathway for amyloid-related diseases like type II diabetes.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Medicine
Background:
- Amyloid fiber formation is linked to diseases such as Alzheimer's, Parkinson's, and type II diabetes.
- While fibrillar deposits characterize these disorders, smaller oligomeric species are increasingly implicated in cellular dysfunction and death.
- The exact mechanism of cell damage by oligomers, likely involving membrane interactions, remains unclear.
Purpose of the Study:
- To investigate the role of islet amyloid polypeptide (IAPP) in the loss of insulin-secreting cells in type II diabetes.
- To identify and characterize oligomeric species of IAPP formed on biological membranes.
- To elucidate the mechanism by which these oligomers disrupt cell membrane integrity.
Main Methods:
- Utilized a combination of ensemble and single-particle evaluation techniques.
- Investigated the stochastic nucleation and assembly of IAPP oligomers on membranes.
- Characterized the stability, leakage properties, and kinetic pathway of IAPP oligomer formation.
Main Results:
- Discovered novel oligomeric IAPP species that form via stochastic nucleation on membranes.
- Demonstrated that these oligomers disrupt the lipid bilayer, causing "all-or-none" leakage.
- Identified a three-state kinetic framework for IAPP assembly, suggesting a non-amyloid intermediate.
Conclusions:
- Oligomeric IAPP species are directly involved in disrupting cell membranes, contributing to cell loss in type II diabetes.
- The identified three-state kinetic model provides a more comprehensive understanding of IAPP assembly on membranes.
- A previously identified non-amyloid intermediate in the IAPP pathway may represent a viable therapeutic target for type II diabetes.
Related Concept Videos
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
01:21Acute Pancreatitis II: Pathophysiology
The pathophysiology of acute pancreatitis centers on injury to pancreatic acinar cells, which initiates a cascade of harmful intracellular events.This injury leads to premature activation of trypsinogen to trypsin in the pancreas. Trypsin then activates other digestive enzymes, such as chymotrypsin, elastase, and phospholipase A2, which begin breaking down pancreatic tissue. The resulting autodigestion causes local inflammation, tissue swelling, hemorrhage, and fat necrosis.Injured acinar cells...
01:21Chronic Pancreatitis II: Pathophysiology
Chronic pancreatitis is a progressive and irreversible inflammation of the pancreas, most often caused by long-term alcohol abuse, but it can also be related to ductal obstruction, smoking, or genetic factors.Chronic pancreatitis occurs when the pancreas is repeatedly exposed to harmful agents like alcohol, smoking, ductal obstruction, or genetic predisposition. These factors lead to the release of toxic metabolites and inflammatory cytokines, sustaining chronic inflammation in the pancreatic...
01:27Glucose Homeostasis: Pancreatic Islets and Insulin Secretion
The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are co-secreted in...
Insulin and C-peptide are co-secreted in...
01:35Asymmetric Lipid Bilayer
Biological membranes show uneven distribution of different types of lipids in the inner and outer layers, resulting in transverse asymmetric membranes. The treatment of the erythrocyte membrane with the enzyme phospholipase confirmed the asymmetric nature of the lipid bilayer. The enzyme hydrolyzes lipids into fatty acids and hydrophilic groups. The phospholipase acts only on the outer layer of the membrane, while the inner layer remains intact. The phospholipase treatment resulted in 80%...
01:05Insulin Secretory Vesicles
Insulin secretory vesicles release insulin to stimulate blood glucose uptake and regulate carbohydrate metabolism. When the blood glucose levels increase, glucose enters the pancreatic β-islet cells through glucose transporters. Once inside, glucose is metabolized through glycolysis, the citric acid cycle, and the electron transport chain, producing ATP. This increase in ATP concentration closes ATP-sensitive potassium channels, leading to depolarization of the membrane and the opening of...