VIB Department of Developmental Molecular Genetics and Katholieke Universiteit Leuven Department of Human Genetics, Heerestraat 49, 3000 Leuven, Belgium.
Neurobiol Aging. 2011 May;32(5):933-43. doi: 10.1016/j.neurobiolaging.2009.04.022. Epub 2009 Jun 3.
Aged neurons constitute an outstanding example of survival robustness, outliving the accumulation of reactive oxygen species (ROS) derived from various physiological activities. Since during aging hippocampal neurons experience a progressive loss of membrane cholesterol and, by virtue of this, a gradual and sustained increase in the activity of the survival receptor tyrosine kinase TrkB, we have tested in this study if cholesterol loss is functionally associated to survival robustness during aging. We show that old neurons that did not undergo the cholesterol drop, upon knockdown of the cholesterol hydroxylating enzyme Cyp46, presented low TrkB activity and increased apoptotic levels. In further agreement, inducing cholesterol loss in young neurons led to the early appearance of TrkB activity. In vivo, Cyp46 knockdown led to the appearance of damaged hippocampal neurons in old mice exposed to exogenous stressful stimuli. Cholesterol loss seems therefore to contribute to neuronal survival in conditions of prominent stress, either acute or chronic. The relevance of this pathway in health and disease is discussed.
衰老神经元是生存韧性的突出范例，它们能够在各种生理活动产生的活性氧（ROS）积累的情况下存活下来。由于在衰老过程中，海马神经元经历了膜胆固醇的逐渐丧失，并且由此导致了生存受体酪氨酸激酶 TrkB 的活性逐渐持续增加，因此我们在这项研究中测试了胆固醇的丧失是否与衰老过程中的生存韧性具有功能相关性。我们发现，那些没有经历胆固醇下降的衰老神经元，在胆固醇羟化酶 Cyp46 被敲低后，表现出低 TrkB 活性和增加的凋亡水平。进一步的一致性表明，在年轻神经元中诱导胆固醇丧失会导致 TrkB 活性的早期出现。在体内，Cyp46 敲低会导致在暴露于外源性应激刺激的老年小鼠中出现受损的海马神经元。因此，胆固醇的丧失似乎有助于在突出的应激条件下，无论是急性还是慢性应激下神经元的存活。讨论了该途径在健康和疾病中的相关性。
