A detergent-insoluble membrane compartment contains A beta in vivo.
Ordered assembly of the amyloid-beta protein (A beta) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide A beta from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, beta-secretase cleaves close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain. The sites of gamma-secretase cleavage are after residues 40 or 42 of A beta. Except in those rare cases of AD caused by a mutation, levels of secreted A beta are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of A beta may contribute to the aggregation properties of the peptide. A beta is also present in intracellular compartments. The two gamma-secretase cleavage products, A beta42 and A beta40, were found in different compartments: A beta42 in the endoplasmic reticulum (ER)/intermediate compartment, and A beta40 in the trans-Golgi network (TGN). The cellular compartments that harbor A beta are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which A beta resides is a detergent-insoluble glycolipid-enriched membrane domain (DIG). Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP. The presence of these proteins, which all contribute to the generation of A beta, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.
Lee
S J
SJ
Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, HIM, Boston, Massachusetts 02115, USA.
Liyanage
U
U
Bickel
P E
PE
Xia
W
W
Lansbury
P T
PT
Kosik
K S
KS
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D016466:CHO Cells; D051242:Caveolin 1; D022461:Caveolins; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003902:Detergents; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051242:Caveolin 1; D022461:Caveolins; D003902:Detergents; D006017:Glycolipids; D008565:Membrane Proteins; C106354:flotillins; D002784:Cholesterol