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      Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

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          Abstract

          Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.

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          Most cited references 68

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          Cleavage of structural proteins during the assembly of the head of bacteriophage T4.

           U K Laemmli (1970)
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            RADIOAUTOGRAPHIC STUDIES OF CHOLINE INCORPORATION INTO PERIPHERAL NERVE MYELIN

            This radioautographic study was designed to localize the cytological sites involved in the incorporation of a lipid precursor into the myelin and the myelin-related cell of the peripheral nervous system. Both myelinating and fully myelinated cultures of rat dorsal root ganglia were exposed to a 30-min pulse of tritiated choline and either fixed immediately or allowed 6 or 48 hr of chase incubation before fixation. After Epon embedding, light and electron microscopic radioautograms were prepared with Ilford L-4 emulsion. Analysis of the pattern of choline incorporation into myelinating cultures indicated that radioactivity appeared all along the length of the internode, without there being a preferential site of initial incorporation. Light microscopic radioautograms of cultures at varying states of maturity were compared in order to determine the relative degree of myelin labeling. This analysis indicated that the myelin-Schwann cell unit in the fully myelinated cultures incorporated choline as actively as did this unit in the myelinating cultures. Because of technical difficulties, it was not possible to determine the precise localization of the incorporated radioactivity within the compact myelin. These data are related to recent biochemical studies indicating that the mature myelin of the central nervous system does incorporate a significant amount of lipid precursor under the appropriate experimental conditions. These observations support the concept that a significant amount of myelin-related metabolic activity occurs in mature tissue; this activity is considered part of an essential and continuous process of myelin maintenance and repair.
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              Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

              The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                6 January 2003
                : 160
                : 1
                : 113-123
                Affiliations
                [1 ]Max Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden, Germany
                [2 ]Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilians University, D-80336 Munich, Germany
                Author notes

                Address correspondence to Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany. Tel.: 49-351-2102800. Fax: 49-351-2102900. E-mail: simons@ 123456mpi-cbg.de

                Article
                200207113
                10.1083/jcb.200207113
                2172747
                12515826
                Copyright © 2003, The Rockefeller University Press
                Categories
                Article

                Cell biology

                lipid rafts; β-amyloid; bace; alzheimer's disease; endocytosis

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