Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.

随着全世界人口的老龄化，认知功能障碍，痴呆和阿尔茨海默氏病（AD）越来越多。对于这些病症的治疗是未得到满足的需求。这篇综述着重于正调节GABA-A受体调节类固醇allopregnanolone（APα）的作用，它在认知和AD受损的潜在机制中的作用，以及确定AD治疗的选择。一方面，间歇给予APα可以促进神经发生，减少与AD有关的病理，并改善认知。另一方面，持续暴露于APα会损害认知并恶化AD病理。这两个结果之间的差异导致我们的小组分析了造成差异的机制。我们得出的结论是，APα的作用取决于给药方式，并且长期略微增加的APα暴露量对认知功能有害并会使AD病理恶化，而间隔较长的单次给药可改善认知并降低AD病理。这些协作评估为APα和APα拮抗剂对AD的治疗开发提供了见识，并为旨在为人类临床试验生成可翻译数据的跨实验室协作提供了模型。