Abstract
Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer's disease, is generated by presenilin-dependent gamma-secretase cleavage of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate Abeta degradation. Presenilin-deficient cells fail to degrade Abeta and have drastic reductions in the transcription, expression, and activity of neprilysin, a key Abeta-degrading enzyme. Neprilysin activity and expression are also lowered by gamma-secretase inhibitors and by PS1/PS2 deficiency in mouse brain. Neprilysin activity is restored by transient expression of PS1 or PS2 and by expression of the amyloid intracellular domain (AICD), which is cogenerated with Abeta, during gamma-secretase cleavage of betaAPP. Neprilysin gene promoters are transactivated by AICDs from APP-like proteins (APP, APLP1, and APLP2), but not by Abeta or by the gamma-secretase cleavage products of Notch, N- or E- cadherins. The presenilin-dependent regulation of neprilysin, mediated by AICDs, provides a physiological means to modulate Abeta levels with varying levels of gamma-secretase activity.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / pharmacology
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Amyloid beta-Peptides / physiology*
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Amyloid beta-Protein Precursor / chemistry
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Amyloid beta-Protein Precursor / deficiency
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Amyloid beta-Protein Precursor / physiology*
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Animals
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Blotting, Western / methods
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Cadherins / metabolism
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Cells, Cultured
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Cloning, Molecular / methods
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Drug Interactions
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Electrophoretic Mobility Shift Assay / methods
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Extracellular Space / metabolism*
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Female
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fluorescent Antibody Technique / methods
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Humans
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Middle Aged
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Models, Biological
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Mutagenesis / physiology
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Neprilysin / genetics
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Neprilysin / metabolism*
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Peptide Fragments / pharmacology
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Promoter Regions, Genetic / physiology
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Protein Processing, Post-Translational / drug effects
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Protein Processing, Post-Translational / physiology*
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Protein Structure, Tertiary / physiology
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Receptors, Notch
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Recombinant Proteins
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Time Factors
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Transfection
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Aplp1 protein, mouse
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Cadherins
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Enzyme Inhibitors
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Membrane Proteins
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Peptide Fragments
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Receptors, Notch
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Recombinant Proteins
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amyloid beta-protein (1-42)
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Neprilysin