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The Journal of Neuroscience, June 1, 2003, 23(11):4560-4566

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Amyloid Precursor Protein Associates with a Nicastrin-Dependent Docking Site on the Presenilin 1–{gamma}-Secretase Complex in Cells Demonstrated by Fluorescence Lifetime Imaging

Oksana Berezovska,1 Pavan Ramdya,1 Jesse Skoch,1 Michael S. Wolfe,2 Brian J. Bacskai,1 and Bradley T. Hyman

1 Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, and 2 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115

{gamma}-Secretase cleavage is the final enzymatic step generating {beta}-amyloid via intramembranous cleavage of the amyloid precursor protein (APP). Presenilin (PS), initially identified as a gene in which mutations account for the vast majority of early-onset autosomal dominant Alzheimer's disease, is a major component of {gamma}-secretase. Enzymatic activity also depends on nicastrin, Aph-1, and Pen-2. We propose a model in which {gamma}-secretase components assemble, interact with substrates initially at a docking site, and then cleave and release substrates. To test this model, we developed a novel morphological technique on the basis of advanced fluorescence microscopy methods, fluorescence lifetime imaging microscopy (FLIM). FLIM allows us to examine protein–protein "proximity" in intact cells. We show that, although the strongest colocalization of APP and PS1 is in the perinuclear area, the strongest interactions detected by FLIM are at or near the cell surface. We also found that APP–PS1 interactions occur even when{gamma}-secretase inhibitors or "dominant-negative" PS1 mutations are used to block {gamma}-secretase activity. Finally, using nicastrin RNA interference, we demonstrate that nicastrin is critical for APP association with PS1. We interpret these results to suggest that there is a noncatalytic docking site closely associated with PS1–{gamma}-secretase.

Key words: APP; nicastrin; presenilin; {gamma}-secretase; docking site; FLIM; spatial paradox

Received Jan. 8, 2003; revised Mar. 20, 2003; accepted Mar. 21, 2003.




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