Presenilin-1 uses phospholipase D1 as a negative regulator of β-amyloid formation

Presenilin (PS1/PS2) is a major component of gamma-secretase, the activity that mediates proteolysis of P-amyloid precursor protein to generate beta-amyloid (A beta). Here we demonstrate that PSI, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network. Overexpression of wildtype PLD1 reduces A beta generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates A beta production. The A beta-lowering effect of PLD1 is independent of its ability to promote vesicular budding of p-amyloid precursor protein. The data indicate that overexpression of PLD1 decreases, and downregulation of PLD1 increases, the catalytic activity, and the association of the subunits, of gamma-secretase.