Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients

Gunter P. Eckert, Gero P. Hooff, Dana M. Strandjord, Urule Igbavboa, Dietrich A. Volmer, Walter E. Müller, W. Gibson Wood

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)251-257
Number of pages7
JournalNeurobiology of Disease
Volume35
Issue number2
DOIs
StatePublished - Aug 2009

Bibliographical note

Funding Information:
This work was supported in part by the Hanna Bragard-Apfel foundation, the Human Brain and Spinal Fluid Resource Center, West Los Angeles, USA, the, Medical Research Council, NIH grants AG23524, AG18357 and the Department of Veterans Affairs.

Keywords

  • Alzheimer disease
  • Cholesterol
  • Farnesylpyrophosphate
  • GTPases
  • Geranylgeranylpyrophosphate
  • HMG-CoA reductase
  • Isoprenoids
  • Prenylation
  • Statins

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