Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients.
Post-translational modification of small GTPases by farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP) has generated much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. Prenylated proteins have been identified in numerous cell functions and elevated levels of FPP and GGPP have been previously proposed to occur in Alzheimer disease (AD) but have never been quantified. In the present study, we determined if the mevalonate derived compounds FPP and GGPP are increased in brain grey and white matter of male AD patients as compared with control samples. This study demonstrates for the first time that FPP and GGPP levels are significantly elevated in human AD grey and white matter but not cholesterol, indicating a potentially disease-specific targeting of isoprenoid regulation independent of HMG-CoA-reductase. Further suggesting a selective disruption of FPP and GGPP homeostasis in AD, we show that inhibition of HMG-CoA reductase in vivo significantly reduced FPP, GGPP and cholesterol abundance in mice with the largest effect on the isoprenoids. A tentative conclusion is that if indeed regulation of FPP and GGPP is altered in AD brain such changes may stimulate protein prenylation and contribute to AD neuropathophysiology.
Eckert
Gunter P
GP
Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Campus Riedberg, Max-von-Laue-St. 9, Frankfurt 60438, Germany. g.p.eckert@em.uni-frankfurt.de
Hooff
Gero P
GP
Strandjord
Dana M
DM
Igbavboa
Urule
U
Volmer
Dietrich A
DA
Müller
Walter E
WE
Wood
W Gibson
WG
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D051228:Geranyltranstransferase / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology
D000214:Acyl Coenzyme A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D019821:Simvastatin; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase; C002963:geranylgeranyl pyrophosphate