Intracellular accumulation of β-amyloid in cells expressing the Swedish mutant amyloid precursor protein

Abstract

β-Amyloid (βA) is a normal metabolic product of the amyloid precursor protein (APP) that accumulates in senile plaques in Alzheimer's disease. Cells that express the Swedish mutant APP (Sw-APP) associated with early onset Alzheimer's disease overproduce βA. In this report, we show that expression of Sw-APP gives rise to cell-associated βA, which is not detected in cells that express wild-type APP. Cell-associated βA is rapidly generated, is trypsin-resistant, and is not derived from βA uptake, indicating that it is generated from intracellular processing of Sw-APP. Intracellular and secreted βA are produced with different kinetics. The generation of intracellular βA is partially resistant to monensin and a 20 °C temperature block but is completely inhibited by brefeldin A, suggesting that it occurs in the Golgi complex. Monensin, brefeldin A, and a 20 °C temperature block almost completely inhibit βA secretion without causing increased cellular retention of βA, suggesting that secreted βA is generated in a post-Golgi compartment. These results suggest that the metabolism of Sw-APP gives rise to intracellular and secreted forms of βA through distinct processing pathways. Pathological conditions may therefore alter both the level and sites of accumulation of βA. It remains to be determined whether the intracellular form of βA plays a role in the formation of amyloid plaques.