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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG015916-05S1
Application #
6925289
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Sierra, Felipe
Project Start
1998-08-01
Project End
2004-11-30
Budget Start
2004-08-01
Budget End
2004-11-30
Support Year
5
Fiscal Year
2004
Total Cost
$37,540
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Li, Xinyi; Masliah, Eliezer; Reixach, Natàlia et al. (2011) Neuronal production of transthyretin in human and murine Alzheimer's disease: is it protective? J Neurosci 31:12483-90
Buxbaum, Joel N (2009) Animal models of human amyloidoses: are transgenic mice worth the time and trouble? FEBS Lett 583:2663-73
Reixach, Natalia; Foss, Ted R; Santelli, Eugenio et al. (2008) Human-murine transthyretin heterotetramers are kinetically stable and non-amyloidogenic. A lesson in the generation of transgenic models of diseases involving oligomeric proteins. J Biol Chem 283:2098-107
Buxbaum, Joel N; Ye, Zhengyi; Reixach, Natalia et al. (2008) Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci U S A 105:2681-6
Tagoe, Clement E; Reixach, Natalia; Friske, Linsey et al. (2007) In vivo stabilization of mutant human transthyretin in transgenic mice. Amyloid 14:227-36
Buxbaum, Joel N (2004) The systemic amyloidoses. Curr Opin Rheumatol 16:67-75
Alexander, Alice; Subramanian, Nivedita; Buxbaum, Joel N et al. (2004) Drop-in, drop-out allele-specific PCR: a highly sensitive, single-tube method. Mol Biotechnol 28:171-4
Reixach, Natalia; Deechongkit, Songpon; Jiang, Xin et al. (2004) Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci U S A 101:2817-22
Tagoe, Clement E; French, David; Gallo, Gloria et al. (2004) Amyloidogenesis is neither accelerated nor enhanced by injections of preformed fibrils in mice transgenic for wild-type human transthyretin: the question of infectivity. Amyloid 11:21-6
Buxbaum, Joel; Tagoe, Clement; Gallo, Gloria et al. (2003) The pathogenesis of transthyretin tissue deposition: lessons from transgenic mice. Amyloid 10 Suppl 1:2-6

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