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JCS ePress
online publication date 26 Jun 2003
doi: 10.1242/jcs.00643
Research Article
Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes
Ayae Kinoshita,
Hiroaki Fukumoto,
Tejal Shah,
Christa M. Whelan,
Michael C. Irizarry,
and
Bradley T. Hyman*
* Author for correspondence (e-mail: bhyman{at}partners.org)
Amyloid-
peptide, which accumulates in senile plaques in Alzheimer's disease, is derived from the amyloid precursor protein (APP) by proteolytic processing. -secretase (Asp2), which cleaves APP at the N-terminus of amyloid-, has recently been identified to be the protease BACE. In the present study, we examined the subcellular localization of interactions between APP and BACE by using both double immunofluorescence and a fluorescence resonance energy transfer (FRET) approach. Cell surface APP and BACE, studied by using antibodies directed against their ectodomains in living H4 neuroglioma cells co-transfected with APP and BACE, showed exquisite co-localization and demonstrated a very close interaction by FRET analysis. The majority of cell surface APP and BACE were internalized after 15 minutes, but they remained strongly co-localized together in the early endosomal compartment, where FRET analysis demonstrated a continued close interaction. By contrast, at later timepoints, almost no co-localization or FRET was observed in lysosomal compartments. To determine whether the APP-BACE interaction on cell surface and endosomes contributed to amyloid- synthesis, we labeled cell surface APP and demonstrated detectable levels of labeled amyloid- within 30 minutes. APP-Swedish mutant protein enhanced amyloid- synthesis from cell surface APP, consistent with the observation that it is a better BACE substrate than wild-type APP. Taken together, these data confirm a close APP-BACE interaction in early endosomes, and highlight the cell surface as an additional potential site of APP-BACE interaction.
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