Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma.

Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma. Research Abstract Details 

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Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma. Abstract Text:

Yan Zhou,Anitha Suram,Chitra Venugopal,Annamalai Prakasam,Suizhen Lin,Yuan Su,Baolin Li,Steven M Paul,Kumar Sambamurti,Yan Zhou,Anitha Suram,Chitra Venugopal,Annamalai Prakasam,Suizhen Lin,Yuan Su,Baolin Li,Steven M Paul,Kumar Sambamurti,Yan Zhou,Anitha Suram,Chitra Venugopal,Annamalai Prakasam,Suizhen Lin,Yuan Su,Baolin Li,Steven M Paul,Kumar Sambamurti,

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.

Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma. Publishing Authors By Initials

Y Zhou,A Suram,C Venugopal,A Prakasam,S Lin,Y Su,B Li,SM Paul,K Sambamurti,Y Zhou,A Suram,C Venugopal,A Prakasam,S Lin,Y Su,B Li,SM Paul,K Sambamurti,Y Zhou,A Suram,C Venugopal,A Prakasam,S Lin,Y Su,B Li,SM Paul,K Sambamurti,

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Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The FASEB journal : official publication of the Fe

VOLUME: 22

Page Numbers: 47-54

Journal Abbreviation: FASEB J.

ISSN: 1530-6860

DAY: 31

MONTH: 07

YEAR: 2007

Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma. Information

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LANGUAGE: eng

NlmUniqueID: 8804484

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Grant and Affiliation Information for Geranylgeranyl pyrophosphate stimulates gamma-secretase to increase the generation of A and APP-CTFgamma.

AFFILIATION: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. Zhou2@iupui.edu

Country: United States

AGENCY: United States NIA

GRANT: AG028544

ACRONYM: AG

MEDLINETA: FASEB J

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