Biphasic effects of insulin on islet amyloid polypeptide membrane disruption.

Type II diabetes, in its late stages, is often associated with the formation of extracellular islet amyloid deposits composed of islet amyloid polypeptide (IAPP or amylin). IAPP is stored before secretion at millimolar concentrations within secretory granules inside the β-cells. Of interest, at these same concentrations in vitro, IAPP rapidly aggregates and forms fibrils, yet within secretory granules of healthy individuals, IAPP does not fibrillize.

Determination of the oligomer size of amyloidogenic protein beta-amyloid(1-40) by single-molecule spectroscopy.

Amyloid diseases are traditionally characterized by the appearance of inter- and intracellular fibrillar protein deposits, termed amyloid. Historically, these deposits have been thought to be the etiology of the disease. However, recent evidence suggests that small oligomers of the amyloidogenic protein/peptide are the origin of neurotoxicity.

Amyloid-beta membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity.

The 40 and 42 residue amyloid-beta (Abeta) peptides are major components of the proteinaceous plaques prevalent in the Alzheimer's disease-afflicted brain and have been shown to have an important role in instigating neuronal degeneration. Whereas it was previously thought that Abeta becomes cytotoxic upon forming large fibrillar aggregates, recent studies suggest that soluble intermediate-sized oligomeric species cause cell death through membrane permeabilization. The present study examines the interactions between Abeta40 and lipid membranes using liposomes as a model system to determine how changes in membrane composition influence the conversion of Abeta into these toxic species.

Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.

Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of beta-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes.