The cytoplasmic sequence of E‐cadherin promotes non‐amyloidogenic degradation of Aβ precursors

The presenilin (PS)/γ‐secretase system promotes production of the Abeta (Aβ) peptides by mediating cleavage of amyloid precursor protein (APP) at the γ‐sites. This system is also involved in the processing of type‐I transmembrane proteins, including APP, cadherins and Notch1 receptors, at the ɛ‐clea...

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Bibliographic Details
Published in:Journal of neurochemistry 2006-02, Vol.96 (4), p.1182-1188
Main Authors: Agiostratidou, Georgia, Muros, Rosa Miñana, Shioi, Junichi, Marambaud, Philippe, Robakis, Nikolaos K.
Format: Article
Language:English
Subjects:
Abeta
Alzheimer's disease
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases
Animals
Binding Sites
Biological and medical sciences
Cadherins - chemistry
Cadherins - physiology
Cell physiology
CHO Cells
Cricetinae
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Endopeptidases - metabolism
E‐cadherin
Fundamental and applied biological sciences. Psychology
lysosomal/endosomal system
Medical sciences
Miscellaneous
Molecular and cellular biology
Neurology
presenilin
Recombinant Proteins - metabolism
Transfection
γ‐secretase
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Summary:The presenilin (PS)/γ‐secretase system promotes production of the Abeta (Aβ) peptides by mediating cleavage of amyloid precursor protein (APP) at the γ‐sites. This system is also involved in the processing of type‐I transmembrane proteins, including APP, cadherins and Notch1 receptors, at the ɛ‐cleavage site, resulting in the production of peptides containing the intracellular domains (ICDs) of the cleaved proteins. Emerging evidence shows that these peptides have important biological functions, raising the possibility that their inhibition by γ‐secretase inhibitors may be detrimental to the cell. Here, we show that peptide E‐Cad/CTF2, produced by the PS1/γ‐secretase processing of E‐cadherin, promotes the lysosomal/endosomal degradation of the transmembrane APP derivatives, C99 and C83, and inhibits production of the APP ICD (AICD). In addition, E‐Cad/CTF2 decreases accumulation of total secreted Aβ. These data suggest a novel method to promote the non‐amyloidogenic degradation of Aβ precursors and to inhibit Aβ production.
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2005.03616.x