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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Sulfation of Phenylephrine by the Human Cytosolic Sulfotransferases
Drug Metabolism Letters Potential Deployment of Angiotensin I Converting Enzyme Inhibitors and of Angiotensin II Type 1 and Type 2 Receptor Blockers in Cancer Chemotherapy
Anti-Cancer Agents in Medicinal Chemistry Calpains as a Target for Therapy of Neurodegenerative Diseases: Putative Role of Lithium
Current Drug Metabolism Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates
Current Topics in Medicinal Chemistry Retinoid Related Molecules an Emerging Class of Apoptotic Agents with Promising Therapeutic Potential in Oncology: Pharmacological Activity and Mechanisms of Action
Current Pharmaceutical Design Endothelial Cell Targeted Molecular Imaging in Tumor Angiogenesis: Strategies and Current Status
Current Pharmaceutical Biotechnology Alternative Splice Variants of Survivin as Potential Targets in Cancer
Current Drug Discovery Technologies Meet Our Editorial Board Member
Letters in Drug Design & Discovery Strategic Aspects of NPY-Based Monoclonal Antibodies for Diagnosis and Treatment of Breast Cancer
Current Protein & Peptide Science Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer's and Parkinson's Disease
CNS & Neurological Disorders - Drug Targets Screening Neuroprotective Agents Through 4-hydroxynonenal, Ethanol, High Glucose, Homocysteine, Okadaic Acid, Rotenone, and Oxygen-Glucose Deprivation Induced PC12 Injury Models: A Review
Current Psychopharmacology Pharmacologic Evidence of Green Tea in Targeting Tyrosine Kinases
Current Reviews in Clinical and Experimental Pharmacology Endocannabinoids as Regulators of Transient Receptor Potential (TRP)Channels: a Further Opportunity to Develop New Endocannabinoid-Based Therapeutic Drugs
Current Medicinal Chemistry Cellomics as Integrative Omics for Cancer
Current Proteomics A Current Review of Cypermethrin-Induced Neurotoxicity and Nigrostriatal Dopaminergic Neurodegeneration
Current Neuropharmacology Alzheimer´s Disease and Oxidative Stress: A Review
Current Medicinal Chemistry Cell Cycle and Cancer: The G1 Restriction Point and the G1 / S Transition
Current Genomics Statin-Like Drugs for the Treatment of Brain Cholesterol Loss in Alzheimers Disease
Current Drug Safety Antibody-Based Targeted Interventions for the Diagnosis and Treatment of Skin Cancers
Anti-Cancer Agents in Medicinal Chemistry Antioxidant Properties of Crocus Sativus L. and Its Constituents and Relevance to Neurodegenerative Diseases; Focus on Alzheimer’s and Parkinson’s Disease
Current Neuropharmacology