Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A beta and APP-CTF gamma

Cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in generation of the amyloid-beta protein (A beta), 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 A beta levels mostly by regulating gamma-secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH) in regulating A beta production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of A beta secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of A beta of 42 residues (A beta 42) in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTF gamma (a. k. a. AICD) as well as A beta by stimulating gamma-secretase-mediated cleavage of APP-CTF beta and APP-CTF beta in vitro. Furthermore, GGOH increases the levels of the active gamma-secretase complex in the detergent-insoluble membrane fraction along with its substrates, APP-CTF alpha and APP-CTF beta. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of gamma-secretase activity that can foster production of the pathologically important A beta 42. -Zhou, Y., Suram, A., Venugopal, C., Prakasam, A., Lin, S., Su, Y., Li, B., Paul, S. M., Sambamurti, K. Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A beta and APP-CTF gamma.