Presenilin-1 Uses Phospholipase D1 as a Negative Regulator of β-Amyloid Formation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (6), p.1941-1946
• Main Authors: Cai, Dongming, Netzer, William J., Zhong, Minghao, Lin, Yixin, Du, Guangwei, Frohman, Michael, Foster, David A., Sisodia, Sangram S., Xu, Huaxi, Gorelick, Fred S., Greengard, Paul
• Format: Article
• Language: English
• Subjects: Alzheimers disease; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Animals; Antibodies; Aspartic Acid Endopeptidases; Biological Sciences; Budding; Cell free system; Cell Line; Cellular immunity; Complementary DNA; Down regulation; Endopeptidases - metabolism; Gene Expression Regulation; Humans; Immunoblotting; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Neurons; Neuroscience; Phospholipase D - genetics; Phospholipase D - metabolism; Presenilin-1; Protein Binding; Protein Processing, Post-Translational; Protein Transport; trans-Golgi Network - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510708103

Presenilin (PS1/PS2) is a major component of γ-secretase, the activity that mediates proteolysis of P-amyloid precursor protein to generate β-amyloid (Aβ). Here we demonstrate that PS1, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network. Overexpression of wildtype PLD1 reduces Aβ generation. Conversely, down-regulation of endogenous PLD1 by small hairpin RNA elevates Aβ production. The Aβ-lowering effect of PLD1 is independent of its ability to promote vesicular budding of β-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 γ-secretase.