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PNAS 99 (7): 4697-4702

Copyright © 2002 by the National Academy of Sciences.


A physiologic signaling role for the {gamma}-secretase-derived intracellular fragment of APP

Malcolm A. Leissring*,{dagger}, M. Paul Murphy{ddagger}, Tonya R. Mead*, Yama Akbari*, Michael C. Sugarman*, Mehrdad Jannatipour*, Brigitte Anliker§, Ulrike Müller§, Paul Saftig, Bart De Strooper||, Michael S. Wolfe**, Todd E. Golde{ddagger}, and Frank M. LaFerla*,{ddagger}{ddagger}

*Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; {ddagger}Department of Neuroscience and Pharmacology, Mayo Clinic, Mayo Graduate School, Jacksonville, FL 32224; §Department of Neurochemistry, Max-Planck- Institute for Brain Research, Deutschordenstrasse 46, D-60528 Frankfurt, Germany; Department of Biochemistry, Christian Albrechts Universitat Kiel, Ohlshausenstrasse 40, D-24098 Kiel, Germany; ||Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology, K.U. Leuven, B-3000 Leuven, Belgium; and **Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115

Received for publication January 21, 2002.

Abstract: Presenilins mediate an unusual intramembranous proteolytic activity known as {gamma}-secretase, two substrates of which are the Notch receptor (Notch) and the β-amyloid precursor protein (APP). {gamma}-Secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)] 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.

{dagger} Present address: Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.

{ddagger}{ddagger} To whom reprint requests should be addressed. E-mail: laferla{at}

Edited by Eric M. Shooter, Stanford University School of Medicine, Stanford, CA, and approved February 4, 2002

This paper was submitted directly (Track II) to the PNAS office.

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