Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism*
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Alzheimer Disease / physiopathology
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Amyloid beta-Peptides / biosynthesis
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Brain / metabolism*
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Brain / physiopathology
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Brefeldin A / pharmacology
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Cell Compartmentation / physiology
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Cells, Cultured
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Endoplasmic Reticulum / metabolism*
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Enzyme Inhibitors / pharmacology
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Female
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Fetus
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Humans
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / deficiency*
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Membrane Proteins / genetics
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Mice
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Mice, Knockout
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Neurons / metabolism*
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Peptide Fragments / biosynthesis
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Peptide Fragments / metabolism*
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Pregnancy
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Presenilin-1
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Presenilin-2
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Protein Synthesis Inhibitors / pharmacology
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Stem Cells / cytology
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Stem Cells / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Enzyme Inhibitors
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Membrane Proteins
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PSEN1 protein, human
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PSEN2 protein, human
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Peptide Fragments
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Presenilin-1
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Presenilin-2
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Protein Synthesis Inhibitors
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Brefeldin A