Brain cholesterol turnover required for geranylgeraniol production and learning in mice
- 27 February 2006
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 103 (10), 3869-3874
- https://doi.org/10.1073/pnas.0600316103
Abstract
The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.Keywords
This publication has 41 references indexed in Scilit:
- Recycling Endosomes Supply AMPA Receptors for LTPScience, 2004
- Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down SyndromeJournal of Neuroscience, 2004
- Insig-dependent Ubiquitination and Degradation of Mammalian 3-Hydroxy-3-methylglutaryl-CoA Reductase Stimulated by Sterols and GeranylgeraniolPublished by Elsevier BV ,2003
- Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegenerationJournal of Lipid Research, 2003
- MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trialThe Lancet, 2002
- AMPA Receptor Trafficking and Synaptic PlasticityAnnual Review of Neuroscience, 2002
- Impaired Cued and Contextual Memory in NPAS2-Deficient MiceScience, 2000
- Expression Cloning of an Oxysterol 7α-Hydroxylase Selective for 24-HydroxycholesterolPublished by Elsevier BV ,2000
- Novel Salvage Pathway Utilizing Farnesol and Geranylgeraniol for Protein IsoprenylationBiochemical and Biophysical Research Communications, 1997
- Regulation of the mevalonate pathwayNature, 1990