Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Rep. 2018 Feb 20;22(8):1974-1981. doi: 10.1016/j.celrep.2018.02.001.
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.
恢复成体干细胞功能为衰老大脑的年轻化提供了一个令人兴奋的方法。然而，介导神经发生年轻化的分子机制仍难以捉摸。在这里，我们报告说，酶 ten eleven translocation methylcytosine dioxygenase 2（Tet2），它催化 5-羟甲基胞嘧啶（5hmC）的产生，挽救了与成年神经发生相关的与年龄相关的下降，并增强了小鼠的认知能力。我们在与成年神经发生相关的衰老海马体中检测到 Tet2 表达和 5hmC 水平的降低。通过在海马神经发生龛或成年神经干细胞中消除 Tet2 表达来模拟年轻人的衰老状态，会减少神经发生并损害学习和记忆。在异时性并体再生模型中，海马体 Tet2 的表达得到恢复。在成熟成年海马体神经发生龛中过表达 Tet2 会增加与神经发生过程相关的 5hmC，抵消神经发生与年龄相关的急剧下降，并增强学习和记忆。我们的数据将 Tet2 确定为神经发生年轻化的关键分子介质。
