The amyloidoses are disorders characterized by the deposition of insoluble protein in tissues to an extent sufficient to compromise organ function. The deposits have a fibrillar ultrastructure and bind the dye Congo Red, giving a characteristic appearance under polarized light. The fibrils may be derived from any one of 16 currently known protein precursors of either normal or variant amino acid sequence. Several of these entities, notably pancreatic amyloid (related to Islet Amyloid Polypeptide), Alzheimer's Disease (AbetaPP), Aortic Amyloid (ApoA1) and Senile Cardiac Amyloid (Transthyretin), occur with increasing frequency with increasing age. It is not known what makes these proteins become insoluble under normal physiologic conditions. Data derived from in vitro folding studies of purified amyloid precursors have been used to generate a variety of hypotheses concerning fibrillogenesis, none of which have been tested in vivo. We have produced mice transgenic for a human amyloid precursor (wild type transthyretin) in which the protein is produced over the life of the animal, yet does not form amyloid deposits until mid- to late adulthood, mirroring the experience in the human disease and allowing the analysis of the relationship between amyloid deposition and aging. In addition, the animals also display the same tissue (heart) and gender (male) predilection as is the case in human senile cardiac (systemic) amyloidosis. This recapitulation of age, sex and target organ specificity, as is seen in humans, suggests that the transgenic model will be useful in allowing us to define the pathophysiology of the disease. It is possible that there are elements which may be responsible for maintaining the solubility of circulating proteins under physiologic conditions, but with the passage of time (i.e. aging), they become less functional. Investigation of the model may allow us to identify and study such mechanisms which, in turn, may provide insight into aging and offer potential therapeutic targets in more than one form of human amyloidosis.
Showing the most recent 10 out of 13 publications