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Brain cholesterol turnover required for geranylgeraniol production and learning in mice
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.
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Metadata
- Authors
- Kotti, T. J., Ramirez, D. M. O., Pfeiffer, B. E., Huber, K. M., & Russell, D. W.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2006-02-27
- Volume
- 103
- Issue
- 10
- Pages
- 3869-3874
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2008823657
- Cited by
- 261
- References
- 14
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- closed
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