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First published online 26 June 2003
doi: 10.1242/jcs.00643
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Research Article |
Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
* Author for correspondence (e-mail: bhyman{at}partners.org)
Accepted 30 April 2003
Amyloid-ß peptide, which accumulates in senile plaques in Alzheimer's disease, is derived from the amyloid precursor protein (APP) by proteolytic processing. ß-secretase (Asp2), which cleaves APP at the N-terminus of amyloid-ß, 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-ß synthesis, we labeled cell surface APP and demonstrated detectable levels of labeled amyloid-ß within 30 minutes. APP-Swedish mutant protein enhanced amyloid-ß 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.
Key words: Alzheimer's disease, Amyloid-ß peptide, Amyloid precursor protein, BACE, Co-localization, Fluorescence resonance energy transfer, Endocytosis
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