Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of Abeta and APP-CTFgamma.
Cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in generation of the amyloid-beta protein (Abeta), which is characteristically deposited in the brain of Alzheimer's disease patients. Inhibitors of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (the statins) reduce levels of cholesterol and isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Previous studies have demonstrated that cholesterol increases and statins reduce Abeta levels mostly by regulating beta-secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH) in regulating Abeta production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of Abeta secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of Abeta of 42 residues (Abeta42) in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTFgamma (a.k.a. AICD) as well as Abeta by stimulating gamma-secretase-mediated cleavage of APP-CTFalpha and APP-CTFbeta in vitro. Furthermore, GGOH increases the levels of the active gamma-secretase complex in the detergent-insoluble membrane fraction along with its substrates, APP-CTFalpha and APP-CTFbeta. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of gamma-secretase activity that can foster production of the pathologically important Abeta42.
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. Zhou2@iupui.edu
Yan
Y
Zhou
Anitha
A
Suram
Chitra
C
Venugopal
Annamalai
A
Prakasam
Suizhen
S
Lin
Yuan
Y
Su
Baolin
B
Li
Steven M
SM
Paul
Kumar
K
Sambamurti
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D011106:Polyisoprenyl Phosphates; C441641:amyloid precursor protein carboxyl-terminal fragment gamma; D008148:Lovastatin; D053829:Amyloid Precursor Protein Secretases; C002963:geranylgeranyl pyrophosphate