Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
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DOI：
10.1016/j.celrep.2018.02.001
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发表时间：
2018-02-20
期刊：
影响因子：
8.8
通讯作者：
Villeda SA
中科院分区：
文献类型：
--
作者：
Gontier G;Iyer M;Shea JM;Bieri G;Wheatley EG;Ramalho-Santos M;Villeda SA
恢复成人干细胞的功能为恢复老化的大脑提供了一种令人兴奋的方法。然而，调节神经源性再生的分子机制仍然难以捉摸。在这里，我们报道了催化5-羟甲基胞嘧啶(5hmC)产生的酶1011易位甲基胞嘧啶双加氧酶2(TET2)，挽救了成年神经发生的年龄相关性衰退，并提高了小鼠的认知能力。我们发现老年大鼠海马区TET2表达和5hmC水平降低，与成年大鼠神经发生有关。通过取消TET2在海马神经源性壁龛或成年神经干细胞中的表达来模拟年轻人的衰老状态，会减少神经发生和学习和记忆受损。在异慢性异种复壮模型中，海马区TET2表达恢复。TET2在成熟成人的海马神经源性壁龛中的过度表达增加了与神经发生过程相关的5hmC，抵消了与年龄相关的神经发生的急剧下降，并增强了学习和记忆。我们的数据表明，TET2是神经原性再生的关键分子介质。Gontier等人的研究成果。找到TET2和神经性再生之间的联系。与年龄相关的海马区TET2和5hmC的缺失与神经发生的减少有关。在幼年小鼠的海马区模仿与年龄相关的TET2的丢失会减少神经发生并损害认知。在成熟的海马体中恢复TET2可以恢复再生能力，增强认知能力。
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. Gontier et al. find a link between Tet2 and neurogenic rejuvenation. Age-related loss of hippocampal Tet2 and 5hmC associates with decreased neurogenesis. Mimicking age-related loss of Tet2 in the young mouse hippocampus decreases neurogenesis and impairs cognition. Restoring Tet2 in the mature hippocampus rejuvenates regenerative capacity and enhances cognition.
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影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
16.2
作者：
Kaas GA;Zhong C;Eason DE;Ross DL;Vachhani RV;Ming GL;King JR;Song H;Sweatt JD
通讯作者：
Sweatt JD
影响因子：
64.5
作者：
Cimmino L;Dolgalev I;Wang Y;Yoshimi A;Martin GH;Wang J;Ng V;Xia B;Witkowski MT;Mitchell-Flack M;Grillo I;Bakogianni S;Ndiaye-Lobry D;Martín MT;Guillamot M;Banh RS;Xu M;Figueroa ME;Dickins RA;Abdel-Wahab O;Park CY;Tsirigos A;Neel BG;Aifantis I
通讯作者：
Aifantis I
影响因子：
25
作者：
Szulwach KE;Li X;Li Y;Song CX;Wu H;Dai Q;Irier H;Upadhyay AK;Gearing M;Levey AI;Vasanthakumar A;Godley LA;Chang Q;Cheng X;He C;Jin P
通讯作者：
Jin P
DOI：
10.1126/science.1251152
发表时间：
2014-05-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Sinha M;Jang YC;Oh J;Khong D;Wu EY;Manohar R;Miller C;Regalado SG;Loffredo FS;Pancoast JR;Hirshman MF;Lebowitz J;Shadrach JL;Cerletti M;Kim MJ;Serwold T;Goodyear LJ;Rosner B;Lee RT;Wagers AJ
通讯作者：
Wagers AJ