title: Intracellular accumulation of beta-amyloid in cells expressing the Swedish mutant amyloid precursor protein.
abstract: 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.
authors.affiliation: Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Martin
authors.forename: G
authors.initials: G
authors.lastname: Schrader-Fischer
authors.forename: J
authors.initials: J
authors.lastname: Busciglio
authors.forename: M
authors.initials: M
authors.lastname: Duke
authors.forename: P
authors.initials: P
authors.lastname: Paganetti
authors.forename: B A
authors.initials: BA
authors.lastname: Yankner
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor