AMYLOID BETA-PROTEIN(25-35) INCREASES CELLULAR APP AND INHIBITS THE SECRETION OF APPS IN HUMAN EXTRANEURONAL CELLS

Amyloid beta-protein (A beta) is the core component of the senile plaq ues occurring during Alzheimer's disease and in its aggregated form is cytotoxic for neuronal and extraneuronal cells. In this study, the in fluence of the spontaneously aggregating fragment A beta(25-35) on the expression and metabolism of beta-amyloid precursor protein (APP) was investigated in human extraneuronal cells. Cellular extracts and cond itioned supernatants were analyzed by immunoblotting. A beta(25-35) st rongly increased the cellular content of APP in cultured epithelial ce lls from thyroid glands and kidneys as well as in the promyelogranuloc ytotic cell line HL-60. At the same time A beta reduced the secretion of soluble APPs to less than one-third of its control value, but did n ot alter the secretion of fibronectin, which was used as a control pro tein. Despite these changes, APP transcription was not changed followi ng A beta(25-35) treatment. These results demonstrate that A beta(25-3 5) strongly increases the APP content of extraneuronal cells by inhibi ting its secretory processing. This may result in a deviation of APP m etabolism towards an internal, potentially amyloidogenic pathway. (C) 1997 Academic Press.