LOCALIZATION AND REGULATED RELEASE OF ALZHEIMER AMYLOID PRECURSOR-LIKE PROTEIN IN THYROCYTES

BACKGROUND: Dysregulation in the processing of the Alzheimer precursor protein (APP) is thought to be central to the deposition of the beta- A4 peptide and to the pathogenesis of Alzheimer's disease. Expression and release of APP has also been known to mediate cell-matrix interact ions and to participate in the regulation of cell proliferation. It ha s also been shown that APP is a member of a family of closely related proteins. This family comprises different splice-forms of APP and APP- like proteins (APP/APLP). Because of the specific processing of export able proteins, thyrocytes represent a particularly useful cell type fo r the study of the processing of APP/APLP (especially proteolysis and iodination) as an indication of cell surface expression and for the st udy of the regulation of these functions. EXPERIMENTAL DESIGN: Rats we re treated in vivo with propylthiouracil, which is known to cause a ri se of serum thyroid-stimulating hormone (TSH) levels and maximum stimu lation of thyroid function and growth. The expression of APP/APLP was analyzed in rat thyroid tissue and in a continuous cell line (FRTL-5) by immunofluorescence staining and by sodium dodecyl sulfate polyacryl amide gel electrophoresis and immunoblotting. Using FRTL-5 cells, secr etion and turnover were analyzed by biosynthetic radiolabeling and imm unoprecipitation of APP/APLP. RESULTS: APP/APLP was detected in follic le cells and in the follicle lumen of resting thyroid glands. In propy lthiouracil-treated rats, the complete endocytic removal of the lumina l content coincided with the pronounced visualization of APP/APLP in t he extrafollicular space, where it was associated with proliferating e ndothelial cells and fibroblasts. In FRTL-5 cells, APP/APLP was locali zed mainly in the Golgi complex and in compartments along the endocyti c pathway, including lysosomes, where degradation of APP/APLP occurred . Mature and immature forms of APP/APLP became iodinated upon reaching the plasma membrane. Part of the extracellular portion of APP/APLP wa s released by these cells cleavage and secretion mechanisms. CONCLUSIO NS: The observations show the expression, maturation, and secretion of APP/APLP in thyrocytes and the up-regulation of these processes by TS H. Part of the immature APP/APLP appeared on the cell surface as indic ated by its iodination. Apparently, this portion of immature APP/APLP escaped maturation during its transport to the cell surface.