Presenilin-Dependent Transcriptional Control of the Aβ-Degrading Enzyme Neprilysin by Intracellular Domains of βAPP and APLP
Copyright policy )Presenilin-Dependent Transcriptional Control of the Aβ-Degrading Enzyme Neprilysin by Intracellular Domains of βAPP and APLP
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.
- Harvard University United States
- University of Toronto Canada
- French National Centre for Scientific Research France
- University Health Network Canada
- Sorbonne University France
Neuroscience(all), Blotting, Western, Fluorescent Antibody Technique, Electrophoretic Mobility Shift Assay, Amyloid beta-Protein Precursor, Mice, Animals, Humans, Drug Interactions, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cloning, Molecular, Enzyme Inhibitors, Cells, Cultured, Aged, Amyloid beta-Peptides, Membrane Proteins, Fibroblasts, Middle Aged, Cadherins, [SDV] Life Sciences [q-bio], Enzyme Activation, Female, Extracellular Space
Neuroscience(all), Blotting, Western, Fluorescent Antibody Technique, Electrophoretic Mobility Shift Assay, Amyloid beta-Protein Precursor, Mice, Animals, Humans, Drug Interactions, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cloning, Molecular, Enzyme Inhibitors, Cells, Cultured, Aged, Amyloid beta-Peptides, Membrane Proteins, Fibroblasts, Middle Aged, Cadherins, [SDV] Life Sciences [q-bio], Enzyme Activation, Female, Extracellular Space
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