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The Journal of Neuroscience, March 1, 1999, 19(5):1717-1727
The Amyloid Precursor Protein Interacts with Go
Heterotrimeric Protein within a Cell Compartment Specialized in
Signal Transduction
Emmanuel
Brouillet1,
Alain
Trembleau1,
Damien
Galanaud1,
Michel
Volovitch1, 2,
Colette
Bouillot1,
Cécile
Valenza1,
Alain
Prochiantz1, and
Bernadette
Allinquant1
1 Centre National de la Recherche Scientifique, Unité
de Recherche Associée 1414, Ecole Normale Supérieure, 75230 Paris Cedex 05, France, and 2 Université Paris 7, Unité de Formation et de Recherche de Biologie, 75005 Paris,
France
The function of the  -amyloid protein precursor (APP), a
transmembrane molecule involved in Alzheimer pathologies, is poorly understood. We recently reported the presence of a fraction of APP
in cholesterol and sphingoglycolipid-enriched microdomains (CSEM), a
caveolae-like compartment specialized in signal transduction. To
investigate whether APP actually interferes with cell signaling, we
reexamined the interaction between APP and Go
GTPase. In strong contrast with results obtained with reconstituted
phospholipid vesicles (Okamoto et al., 1995), we find that incubating
total neuronal membranes with 22C11, an antibody that recognizes
an N-terminal APP epitope, reduces high-affinity
Go GTPase activity. This inhibition is specific of
G o and is reproduced, in the absence of 22C11, by the
addition of the APP C-terminal domain but not by two distinct
mutated APP C-terminal domains that do not bind Go.
This inhibition of Go GTPase activity by either 22C11 or
wild-type APP cytoplasmic domain suggests that intracellular
interactions between APP and Go could be regulated by
extracellular signals. To verify whether this interaction is preserved
in CSEM, we first used biochemical, immunocytochemical, and
ultrastructural techniques to unambiguously confirm the colocalization of Go and APP in CSEM. We show that inhibition of
basal Go GTPase activity also occurs within CSEM and
correlates with the coimmunoprecipitation of Go and
APP. The regulation of Go GTPase activity by APP
in a compartment specialized in signaling may have important
consequences for our understanding of the physiopathological functions
of APP.
Key words:
APP; Alzheimer's disease; microdomains; signal
transduction; G-proteins; nervous system
Copyright © 1999 Society for Neuroscience 0270-6474/99/1951717-11$05.00/0
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