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J Biol Chem. 2009 May 1;284(18):12145-52. doi: 10.1074/jbc.M808497200. Epub 2009 Mar 10.

Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1.

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  • 1Burnham Institute for Medical Research, La Jolla, California 92037, USA.


Excessive accumulation of beta-amyloid peptides in the brain is a major cause for the pathogenesis of Alzheimer disease. beta-Amyloid is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases, whose enzymatic activities are tightly controlled by subcellular localization. Delineation of how intracellular trafficking of these secretases and APP is regulated is important for understanding Alzheimer disease pathogenesis. Although APP trafficking is regulated by multiple factors including presenilin 1 (PS1), a major component of the gamma-secretase complex, and phospholipase D1 (PLD1), a phospholipid-modifying enzyme, regulation of intracellular trafficking of PS1/gamma-secretase and beta-secretase is less clear. Here we demonstrate that APP can reciprocally regulate PS1 trafficking; APP deficiency results in faster transport of PS1 from the trans-Golgi network to the cell surface and increased steady state levels of PS1 at the cell surface, which can be reversed by restoring APP levels. Restoration of APP in APP-deficient cells also reduces steady state levels of other gamma-secretase components (nicastrin, APH-1, and PEN-2) and the cleavage of Notch by PS1/gamma-secretase that is more highly correlated with cell surface levels of PS1 than with APP overexpression levels, supporting the notion that Notch is mainly cleaved at the cell surface. In contrast, intracellular trafficking of beta-secretase (BACE1) is not regulated by APP. Moreover, we find that PLD1 also regulates PS1 trafficking and that PLD1 overexpression promotes cell surface accumulation of PS1 in an APP-independent manner. Our results clearly elucidate a physiological function of APP in regulating protein trafficking and suggest that intracellular trafficking of PS1/gamma-secretase is regulated by multiple factors, including APP and PLD1.

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