INTRACELLULAR ACCUMULATION OF BETA-AMYLOID IN CELLS EXPRESSING THE SWEDISH MUTANT AMYLOID PRECURSOR PROTEIN

beta-Amyloid (beta A) is a normal metabolic product of the amyloid pre cursor protein (APP) that accumulates in senile plaques in Alzheimer's disease. Cells that express the Swedish mutant APP (Sw-APP) associate d with early onset Alzheimer's disease overproduce beta A, In this rep ort, we show that expression of Sw-APP gives rise to cell-associated b eta A, which is not detected in cells that express wild-type APP, Cell -associated beta A is rapidly generated, is trypsin-resistant, and is not derived from beta A uptake, indicating that it is generated from i ntracellular processing of Sw-APP, Intracellular and secreted beta A a re produced with different kinetics, The generation of intracellular b eta A is partially resistant to monensin and a 20 degrees C temperatur e block but is completely inhibited by brefeldin A, suggesting that it occurs in the Golgi complex, Monensin, brefeldin A, and a 20 degrees C temperature block almost completely inhibit beta A secretion without causing increased cellular retention of beta A, suggesting that secre ted beta A is generated in a post-Golgi compartment, These results sug gest that the metabolism of Sw-APP gives rise to intracellular and sec reted forms of beta A through distinct processing pathways, Pathologic al conditions may therefore alter both the level and sites of accumula tion of beta A It remains to be determined whether the intracellular f orm of beta A plays a role in the formation of amyloid plaques.