Abstract
Cholesterol transport is a key regulator of amyloid precursor protein (APP) processing and β-amyloid (Aβ) production, implicated in Alzheimers disease. Perturbation of cholesterol transport can be pharmacologically induced by the class II amphiphile 3-β-[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 Aβ 1-40 was reduced in U18666a-treated cells. U18666a elevated the steady state level of the APP holoprotein but not APP mRNA levels. U18666a increased sAPPα secretion and intracellular α-CTF/C83 levels but intracellular βCTF/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 β-secretase processing and reduced internalization for α-secretase processing. These data demonstrate that U18666a effects on cholesterol transport function to regulate amyloid precursor protein metabolism and trafficking.
Keywords: Abeta, Alzheimer's disease, U18666a, beta secretase, alpha secretase, amyloid precursor protein, cholesterol, trafficking
Current Alzheimer Research
Title: The Cholesterol Transport Inhibitor U18666a Regulates Amyloid Precursor Protein Metabolism and Trafficking in N2aAPP “Swedish” Cells
Volume: 5 Issue: 5
Author(s): Warren Davis Jr.
Affiliation:
Keywords: Abeta, Alzheimer's disease, U18666a, beta secretase, alpha secretase, amyloid precursor protein, cholesterol, trafficking
Abstract: Cholesterol transport is a key regulator of amyloid precursor protein (APP) processing and β-amyloid (Aβ) production, implicated in Alzheimers disease. Perturbation of cholesterol transport can be pharmacologically induced by the class II amphiphile 3-β-[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 Aβ 1-40 was reduced in U18666a-treated cells. U18666a elevated the steady state level of the APP holoprotein but not APP mRNA levels. U18666a increased sAPPα secretion and intracellular α-CTF/C83 levels but intracellular βCTF/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 β-secretase processing and reduced internalization for α-secretase processing. These data demonstrate that U18666a effects on cholesterol transport function to regulate amyloid precursor protein metabolism and trafficking.
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Cite this article as:
Davis Jr. Warren, The Cholesterol Transport Inhibitor U18666a Regulates Amyloid Precursor Protein Metabolism and Trafficking in N2aAPP “Swedish” Cells, Current Alzheimer Research 2008; 5 (5) . https://dx.doi.org/10.2174/156720508785908900
DOI https://dx.doi.org/10.2174/156720508785908900 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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