Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease

• Published in: Journal of neurochemistry Vol. 113; no. 4; pp. 978 - 989
• Main Authors: Tian, Guilian, Kong, Qiongman, Lai, Liching, Ray-Chaudhury, Abhik, Lin, Chien-liang G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-05-2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Adult and adolescent clinical studies; Aged; Alzheimer disease; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Astrocytes - metabolism; Biochemistry; Biological and medical sciences; Brain - metabolism; Brain - physiopathology; Brain Chemistry - physiology; Cholesterol; Cholesterol - metabolism; Cholesterol 24-Hydroxylase; cholesterol 24S-hydroxylase; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Excitatory Amino Acid Transporter 2 - metabolism; excitotoxicity; glutamate transporter EAAT2; Glutamic Acid - metabolism; Humans; lipid raft microdomain; Medical sciences; Membrane Microdomains - metabolism; Neurology; Neurotransmitters; Organic mental disorders. Neuropsychology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Steroid Hydroxylases - metabolism; Up-Regulation - physiology; Oxidative stress; Alzheimer disease; Neuroglia; Central nervous system; Lipids; Hyperlipoproteinemia; lipid raft microdomain; Clearance; Lipoprotein; Encephalon; Degenerative disease; Degeneration; Dyslipemia; excitotoxicity; Alzheimer's disease; Nervous system diseases; GLT-1 glutamate transporter; cholesterol 24S-hydroxylase; Metabolic diseases; Glutamate; Uptake; Cholesterol; Cerebral disorder; Hypercholesterolemia; Neuron; Central nervous system disease; Plasma membrane; Excitatory aminoacid; Neurotransmitter; Disruption; Neurotransmission; glutamate transporter EAAT2
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06661.x

J. Neurochem. (2010) 113, 978-989. The glial glutamate transporter EAAT2 (excitatory amino acid transporter 2) is the major mediator of glutamate clearance that terminates glutamate-mediated neurotransmission. Loss of EAAT2 and associated glutamate uptake function has been reported in the brains of patients with Alzheimer's disease (AD). We previously reported that EAAT2 is associated with lipid raft microdomains of the plasma membrane. In the present study, we demonstrated that association of EAAT2 with lipid rafts is disrupted in AD brains. This abnormality is not a consequence of neuron degeneration, oxidative stress, or amyloid beta toxicity. In AD brains, cholesterol 24S-hydroxylase (CYP46), a key enzyme in maintenance of cholesterol homeostasis in the brain, is markedly increased in astrocytes but decreased in neurons. We demonstrated that increased expression of CYP46 in primary astrocytes results in a reduction of membrane cholesterol levels and leads to the dissociation of EAAT2 from lipid rafts and the loss of EAAT2 and associated glutamate uptake function. These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD.