title: Cholesterol overload induces apoptosis in SH-SY5Y human neuroblastoma cells through the up regulation of flotillin-2 in the lipid raft and the activation of BDNF/Trkb signaling.
abstract: Epidemiological investigations have shown that Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. It has been indicated that the cholesterol concentration in the brain of AD patients is higher than that in normal people. In this study, we investigated the effects of cholesterol concentrations, 0, as the control, 3.125, 12.5, and 25μM, on cholesterol metabolism, neuron survival, AD-related protein expressions, and cell morphology and apoptosis using SH-SY5Y human neuroblastoma cells. We observed that expressions of cholesterol hydroxylase (Cyp46), flotillin-2 (a marker of lipid raft content), and truncated tyrosine kinase B (TrkBtc) increased, while expressions of brain-derived neurotrophic factor (BDNF) and full-length TrkB (TrkBfl) decreased as the concentration of cholesterol loading increased. Down-regulation of the PI3K-Akt-glycogen synthase kinase (GSK)-3β cascade and cell apoptosis were also observed at higher concentrations of cholesterol, along with elevated levels of β-amyloid (Aβ), β-secretase (BACE), and reactive oxygen species (ROS). In conclusion, we found that cholesterol overload in neuronal cells imbalanced the cholesterol homeostasis and increased the protein expressions causing cell apoptosis, which illustrates the neurodegenerative pathology of abnormally elevated cholesterol concentrations found in AD patients.
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan; Department of Dietetics, MacKay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yen-Ning
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Department of Nutrition and Health Sciences, Kainan University, Taoyuan, Taiwan.
authors.forename: Ching-I
authors.initials: CI
authors.lastname: Lin
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Nutritional Science, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yue-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chiu
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan. Electronic address: lin5611@tmu.edu.tw.
authors.forename: Shyh-Hsiang
authors.initials: SH
authors.lastname: Lin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D000072503:Cytochrome P450 Family 46 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020813:Receptor, trkB; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C106354:flotillins; C579455:BDNF protein, human; D002784:Cholesterol; D000072503:Cytochrome P450 Family 46; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases
keywords: 24-OHC; Alzheimer’s disease; BDNF; Cyp46; PI3K-Akt-GSK-3β; lipid raft