Journal
NEUROBIOLOGY OF DISEASE
Volume 35, Issue 2, Pages 251-257Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2009.05.005
Keywords
Alzheimer disease; HMG-CoA reductase; Isoprenoids; Farnesylpyrophosphate; Geranylgeranylpyrophosphate; Prenylation; GTPases; Cholesterol; Statins
Categories
Funding
- Hanna Bragard-Apfel foundation
- Human Brain and Spinal Fluid Resource Center, West Los Angeles, USA
- Medical Research Council
- NIH [AG23524, AG18357]
- Department of Veterans Affairs
- MRC [MC_U105960396] Funding Source: UKRI
- Medical Research Council [MC_U105960396] Funding Source: researchfish
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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. (C) 2009 Elsevier Inc. All rights reserved.
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