Presenilins are not required for A beta 42 production in the early secretory pathway.
Presenilins 1 and 2 (PS1/PS2) have been suggested to be gamma-secretases responsible for the proteolytic cleavage of amyloid precursor protein (APP) to form amyloid-beta (A beta), a protein implicated in the development of Alzheimer's disease. Here we examined whether these presenilins are required for the generation of multiple A beta species by analyzing the production of several forms of secreted and intracellular A beta in mouse cells lacking PS1, PS2 or both proteins. Although most A beta species were abolished in PS1/PS2(-/-) cells, the production of intracellular A beta 42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. These results indicate that production of this pool of A beta occurs independently of PS1/PS2, and therefore, another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments.
Wilson
Christina A
CA
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Doms
Robert W
RW
Zheng
Hui
H
Lee
Virginia M-Y
VM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D020126:Brefeldin A / Q000494:pharmacology; D002451:Cell Compartmentation / Q000502:physiology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism*; D011247:Pregnancy; D053764:Presenilin-1; D053766:Presenilin-2; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D011500:Protein Synthesis Inhibitors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D020126:Brefeldin A