Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.
Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.
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DOI：
10.1016/j.neurobiolaging.2015.10.035
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发表时间：
2016-02
影响因子：
4.2
通讯作者：
Kessler JA
中科院分区：
文献类型：
--
作者：
Meyers EA;Gobeske KT;Bond AM;Jarrett JC;Peng CY;Kessler JA
衰老与海马体神经发生的减少和海马体依赖性认知功能的减弱有关。小鼠齿状回中骨形态发生蛋白 4 (BMP4) 的表达随着年龄的增长而增加 10 倍以上，而 BMP 抑制剂头蛋白的水平则下降。这导致磷酸化-SMAD1/5/8（经典 BMP 信号传导的效应器）显着增加 30 倍。正如在小鼠中观察到的那样，在没有已知认知异常的人类齿状回中观察到 BMP4 表达显着增加。通过头蛋白过度表达或转基因操作来抑制 BMP 信号传导不仅可以增加衰老小鼠的神经发生，而且值得注意的是，与将认知缺陷恢复到与年轻小鼠相当的水平有关。当 BMP 信号传导抑制与环境富集相结合时，可以观察到附加效益。这些发现表明，BMP 信号传导的增加会显着导致神经发生损伤和与衰老相关的认知能力下降，并将该通路确定为逆转与年龄相关的认知变化的潜在药物靶标。
Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition.