A physiologic signaling role for the γ-secretase-derived intracellular fragment 
of APP

Leissring, M. A.; Murphy, M. P.; Mead, T. R.; Akbari, Y.; Sugarman, M. C.; Jannatipour, M.; Anliker, B.; Müller, U.; Saftig, P.; De Strooper, B.; Wolfe, M. S.; Golde, T. E.; LaFerla, F. M.

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A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP

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Anliker, B.
Neurochemistry Department, Max Planck Institute for Brain Research, Max Planck Society;

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Müller, U.
Neurochemistry Department, Max Planck Institute for Brain Research, Max Planck Society;

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Citation

Leissring, M. A., Murphy, M. P., Mead, T. R., Akbari, Y., Sugarman, M. C., Jannatipour, M., et al. (2002). A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP. Proceedings of the National Academy of Sciences of the United States of America, 99(7), 4697-4702.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-1FB7-1

Abstract

Presenilins mediate an unusual intramembranous proteolytic activity known as gamma-secretase, two substrates of which are the Notch receptor (Notch) and the beta-amyloid precursor protein (APP). gamma-Secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)1 that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of gamma-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and-notably-these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide- mediated calcium signaling through a gamma-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.