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Geranylgeranyl pyrophosphate stimulates -secretase to increase the generation of Aβ and APP-CTF

Yan Zhou^*,1, Anitha Suram^*, Chitra Venugopal^*, Annamalai Prakasam^*, Suizhen Lin, Yuan Su, Baolin Li, Steven M. Paul^,1,2 and Kumar Sambamurti^*,1,2

^* Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA; and

Eli Lilly and Company, Indianapolis, Indiana, USA

¹Correspondence: Y.Z., Herman B. Wells Center for Pediatric Research, R4–331, 1044 W. Walnut, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail: Zhou2{at}iupui.edu; S.M.P., Eli Lilly and Company, Indianapolis, IN 46285, USA. E-mail: paul_steven_m{at}lilly.com; K.S., Department of Neurosciences, MUSC, BSB-403, 173 Ashley Ave., Charleston, SC 29425, USA. E-mail: sambak{at}musc.edu

Cleavage of the amyloid precursor protein (APP) by β- and -secretases results in generation of the amyloid-β protein (Aβ), 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 Aβ levels mostly by regulating β-secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH) in regulating Aβ production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of Aβ secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of Aβ of 42 residues (Aβ42) in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTF (a.k.a. AICD) as well as Aβ by stimulating -secretase-mediated cleavage of APP-CTF and APP-CTFβ in vitro. Furthermore, GGOH increases the levels of the active -secretase complex in the detergent-insoluble membrane fraction along with its substrates, APP-CTF and APP-CTFβ. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of -secretase activity that can foster production of the pathologically important Aβ42.—Zhou, Y., Suram, A., Venugopal, C., Prakasam, A., Lin, S., Su, Y., Li, B., Paul, S. M., Sambamurti, K. Geranylgeranyl pyrophosphate stimulates -secretase to increase the generation of Aβ and APP-CTF.

Key Words: Alzheimer’s disease • statins • mevalonic acid • amyloid precursor protein • AICD • isoprenoid

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