The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture.
The gamma-secretase cleavage is the last step in the generation of the beta-amyloid peptide (Abeta) from the amyloid precursor protein (APP). The Abeta precipitates in the amyloid plaques in the brain of Alzheimer's disease patients. The fate of the intracellular APP carboxy-terminal stub generated together with Abeta has been, in contrast, only poorly documented. The analogies between the processing of APP and other transmembrane proteins like SREBP and Notch suggests that this intracellular fragment could have important signalling functions. We demonstrate here that APP-C59 is rapidly degraded (half-life approximately 5 min) when overexpressed in baby hamster kidney cells or primary cultures of neurones by a mechanism that is not inhibited by endosomal/lysosomal or proteasome inhibitors. Furthermore, APP-C59 binds to the DNA binding protein Fe65, although this does not increase the half-life of APP-C59. Finally, we demonstrate that a fraction of APP-C59 becomes redistributed to the nuclear detergent-insoluble pellet, in which the transcription factor SP1 is also present. Overall our results reinforce the analogy between Notch and APP processing, and suggest that the APP intracellular domain, like the Notch intracellular domain, could have a role in signalling events from the plasma membrane to the nucleus.
Cupers
P
P
Neuronal Cell Biology Group, Center for Human Genetics, Flanders Interuniversitary Institute for Biotechnology and Catholic University of Leuven, Leuven, Belgium.
Orlans
I
I
Craessaerts
K
K
Annaert
W
W
De Strooper
B
B
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D005822:Genetic Vectors; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D053764:Presenilin-1; D051880:Receptors, Notch; D012672:Semliki forest virus / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013347:Subcellular Fractions; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; D051880:Receptors, Notch; D016329:Sp1 Transcription Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse