Brain cholesterol turnover required for geranylgeraniol production and learning in mice

作者: T. J. Kotti , D. M. O. Ramirez , B. E. Pfeiffer , K. M. Huber , D. W. Russell

DOI: 10.1073/PNAS.0600316103

关键词: Mevalonate pathwayGeranylgeraniolCholesterol 24-hydroxylaseHMG-CoA reductaseEndocrinologyMevalonic acidCholesterolInternal medicineLong-term potentiationBiologyStatin

摘要: The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of is metabolized in neurons by enzyme 24-hydroxylase, this depletion activates pathway. Brains from mice lacking 24-hydroxylase excrete more slowly, tissue compensates suppressing Here we report that suppression causes defect learning. 24-Hydroxylase knockout exhibit severe deficiencies spatial, associative, motor learning, hippocampal long-term potentiation (LTP). Acute treatment wild-type slices with an inhibitor (a statin) also impairs LTP. effects statin genetic elimination on LTP are reversed 20-min geranylgeraniol but not cholesterol. We conclude turnover brain constant production small subset required for

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