The cholesterol transport inhibitor U18666a regulates amyloid precursor protein metabolism and trafficking in N2aAPP "Swedish" cells.
Cholesterol transport is a key regulator of amyloid precursor protein (APP) processing and beta-amyloid (Abeta production, implicated in Alzheimer's disease. Perturbation of cholesterol transport can be pharmacologically induced by the class II amphiphile 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one, U18666a; however, the mechanisms by which U18666a controls APP metabolism and trafficking have not been elucidated. We proposed to determine how U18666a regulates APP holoprotein metabolism and trafficking in N2a mouse neuroblastoma cells stably expressing the human APP protein. Secretion of Abeta1-40 was reduced in U18666a-treated cells. U18666a elevated the steady state level of the APP holoprotein but not APP mRNA levels. U18666a increased sAPPalpha secretion and intracellular alpha-CTF/C83 levels but intracellular betaCTF/C99 levels were reduced. The increase in APP protein level was due to decreased catabolism rather than increased APP synthesis. Interestingly, U18666a regulated APP trafficking and increased the level of the holoprotein at the cell surface for alpha-secretase processing and reduced internalization for beta-secretase processing. These data demonstrate that U18666a effects on cholesterol transport function to regulate amyloid precursor protein metabolism and trafficking.
Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA. davisw@musc.edu
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D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000736:Androstenes; D000924:Anticholesteremic Agents; C078201:Aplp1 protein, mouse; D012333:RNA, Messenger; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol