The goal of this project is to determine whether the amylin (IAPP) protein has a role in innate immunity (similar to Abeta) in order to significantly advance our understanding of the origins of diabetes pathology and its possible linkage to Alzheimer’s disease.
The underlying cause of Type 2 diabetes mellitus remains unclear. In 1987, researchers found an important clue to the pathological mechanisms underpinning the disease—insoluble deposits of a small protein called amylin (IAPP) that form in pancreatic islets of those with diabetes. Proteinaceous deposits of this kind are known as amyloid and are a pathological hallmark of a number of common diseases, including Alzheimer’s disease (AD). Different amyloid-forming proteins are associated with different diseases. However, amyloid-forming proteins often share physiochemical properties and their associated diseases overlapping pathologies. The similarities between IAPP and Abeta are particularly striking. Abeta is present in the brains and pancreatic islets of patients with diabetes. Both IAPP and Abeta are small, amphipathic molecules generated by cleavage of larger membrane-associated precursor proteins and bind the molecular chaperone apolipoprotein E. Abeta and IAPP also share another important similarity—despite two decades of intensive study, the normal non-pathogenic functions of these proteins are poorly understood. Our laboratory recently advanced the novel idea that Abeta is part of the innate immune system and belongs to a family of proteins called antimicrobial peptides (AMPs). AMPs function as natural antibiotics to protect against invading pathogens. In vitro Abeta can inhibit the growth of at least eight clinically important pathogens. In addition, homogenates prepared from the brains of AD patients have specific Abeta- mediated antimicrobial activity. Preliminary data from our latest experiments show IAPP also has antimicrobial activity and inhibits the growth of the important human pathogens Candida albicans and Listeria monocytogenes. In initial tests, IAPP antimicrobial activity was equivalent to Abeta, although the peptide may target a narrower microbial spectrum.
Our discovery of Abeta’s role in immunity identifies pharmacological manipulation of the innate immune system as a new and promising therapeutic strategy for treating AD. Strong epidemiologic evidence suggests an association between AD and Type 2 diabetes, but the critical pathological mechanism common to both diseases has yet to be identified. Our preliminary findings link, for the first time, the amyloid-forming proteins of these two disorders with a common non-pathological function as innate immune effector molecules. We propose a project to investigate IAPP for a role in innate immunity using an experimental paradigm similar to that used in the study of Abeta. We think findings from this new line of inquiry may significantly advance our understanding of the origins of diabetes pathology and is potentially the basis for a new therapeutic strategy for curbing the rising diabetes epidemic.