Protofibrillar Islet Amyloid Polypeptide Permeabilizes Synthetic Vesicles by a Pore-like Mechanism that May Be Relevant to Type II Diabetes

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Abstract
Islet amyloid polypeptide (IAPP) and insulin are copackaged and cosecreted by pancreatic islet β-cells. Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by dysfunction and depletion of these β-cells and also, in more than 90% of patients, amyloid plaques containing fibrillar IAPP. An aggregated but not necessarily fibrillar form of IAPP is toxic in cell culture, suggesting that prefibrillar oligomeric (protofibrillar) IAPP may be pathogenic. We report here that IAPP generates oligomeric species in vitro that are consumed as β-sheet-rich fibrils grow. Protofibrillar IAPP, like protofibrillar α-synuclein, which is implicated in Parkinson's disease pathogenesis, permeabilizes synthetic vesicles by a pore-like mechanism. The formation of the IAPP amyloid pore is temporally correlated to the formation of early IAPP oligomers and its disappearance to the appearance of amyloid fibrils. Neither pores nor oligomers were formed by the nonfibrillogenic rat IAPP variant. The IAPP amyloid pore may be critical to the pathogenic mechanism of NIDDM, as other amyloid pores may be to Alzheimer's disease and Parkinson's disease.

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