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 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 beta A. In this report, we show that expression of Sw-APP gives rise to cell-associated beta 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 intracellular processing of Sw-APP. Intracellular and secreted beta A are produced with different kinetics. The generation of intracellular beta A is partially resistant to monensin and a 20 degrees C temperature 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 secreted beta A is generated in a post-Golgi compartment. These results suggest that the metabolism of Sw-APP gives rise to intracellular and secreted forms of beta A through distinct processing pathways. Pathological conditions may therefore alter both the level and sites of accumulation of beta A. It remains to be determined whether the intracellular form of beta A plays a role in the formation of amyloid plaques.
Martin
B L
BL
Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Schrader-Fischer
G
G
Busciglio
J
J
Duke
M
M
Paganetti
P
P
Yankner
B A
BA
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D009154:Mutation; D011499:Protein Processing, Post-Translational; D013696:Temperature
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor