The Alzheimer beta-amyloid precursor protein (APP) is a transmembrane glycoprotein from which the amyloid beta-protein is proteolytically derived. The latter is a hydrophobic peptide that can aggregate and forms the core of the senile plaques found in the brains of patients suffering from Alzheimer's disease (AD). In view of the known association between familial AD and thyroid autoimmune disease, the expression pattern and cellular processing of APP in human thyroid cells were investigated. Cultured thyroid epithelial cells and homogenized thyroid tissue from normal and pathological thyroid samples were analyzed by immunoblotting using specific N- and C-terminal APP antibodies as well as by reverse transcription-polymerase chain reaction in which two sets of oligonucleotide primers were used. The results of these studies demonstrated that APP isoforms 770 and 751 were expressed in fresh thyroid extracts as well as in cultured thyroid epithelial cells, with APP 770 being the predominant form. Compared to other types of cells, such as lymphocytes and fibroblasts, thyroid epithelial cells produced larger amounts of APP. Most of the mature protein was cleaved within the amyloid beta region, as a result of which a large N-terminal APP fragment was released into the culture medium, whereas a C-terminal nonamyloidogenic fragment of 14 kilodaltons (kDa) was retained within the cell. Interestingly, thyroid epithelial cells also contained larger C-terminal APP fragments of 21, 35, and 41 kDa. From the sizes of these fragments it could be deduced that they contained the entire amyloid beta sequence and were thus potentially amyloidogenic. The 41-kDa fragment was unique to thyroid cells. These fragments may be released into the circulation after thyroid cell damage. Increased/altered thyroid APP expression in familiar AD may induce alterations in thyroid epithelial cells and cell damage, and thus explain the frequent occurrence of thyroid autoimmunity in this disease.