tailieunhanh - Báo cáo khoa học: Active c-secretase is localized to detergent-resistant membranes in human brain

Several lines of evidence suggest that polymerization of the amyloidb-pep-tide (Ab) into amyloid plaques is a pathogenic event in Alzheimer’s disease (AD). Abis produced from the amyloid precursor protein as the result of sequential proteolytic cleavages by b-secretase and c-secretase, and it has been suggested that these enzymes could be targets for treatment of AD. | ễFEBS Journal Active c-secretase is localized to detergent-resistant membranes in human brain Ji-Yeun Hur Hedvig Welander Homira Behbahani Mikio Aoki Jenny Franberg Bengt Winblad Susanne Frykman and Lars O. Tjernberg Karolinska Institutet KI Dainippon Sumitomo Pharma Alzheimer Center KASPAC KI-Alzheimer s Disease Research Center Department of Neurobiology Care Sciences and Society Karolinska Institutet Novum Huddinge Sweden Keywords Alzheimer s disease detergent-resistant membranes human brain lipid rafts y-secretase Correspondence L. O. Tjernberg Department of Neurobiology Care Sciences and Society Karolinska Institutet Novum KASPAC Plan 5 141 57 Huddinge Sweden Fax 46 8 585 83610 Tel 46 8 585 83620 E-mail Present address Genomic Science Laboratories Functional Genomics Group Osaka Japan Received 29 October 2007 revised 22 December 2007 accepted 8 January 2008 doi Several lines of evidence suggest that polymerization of the amyloid b-pep-tide Ab into amyloid plaques is a pathogenic event in Alzheimer s disease AD . Ab is produced from the amyloid precursor protein as the result of sequential proteolytic cleavages by b-secretase and c-secretase and it has been suggested that these enzymes could be targets for treatment of AD. c-Secretase is an aspartyl protease complex containing at least four transmembrane proteins. Studies in cell lines have shown that c-secretase is partially localized to lipid rafts which are detergent-resistant membrane microdomains enriched in cholesterol and sphingolipids. Here we studied c-secretase in detergent-resistant membranes DRMs prepared from human brain. DRMs prepared in the mild detergent CHAPSO and isolated by sucrose gradient centrifugation were enriched in c-secretase components and activity. The DRM fraction was subjected to size-exclusion chromatography in CHAPSO and all of the c-secretase components and a lipid raft marker were found in the void volume 2000 kDa . .