J Biol Chem. 2014 Jul 25;289(30):20615-29. doi: 10.1074/jbc.M114.568659.
The mammalian target of rapamycin (mTOR) pathway has multiple important physiological functions, including regulation of protein synthesis, cell growth, autophagy, and synaptic plasticity. Activation of mTOR is necessary for the many beneficial effects of brain-derived neurotrophic factor (BDNF), including dendritic translation and memory formation in the hippocampus. At present, however, the role of mTOR in BDNF's support of survival is not clear. We report that mTOR activation is necessary for BDNF-dependent survival of primary rat hippocampal neurons, as either mTOR inhibition by rapamycin or genetic manipulation of the downstream molecule p70S6K specifically blocked BDNF rescue. Surprisingly, however, BDNF did not promote neuron survival by up-regulating mTOR-dependent protein synthesis or through mTOR-dependent suppression of caspase-3 activation. Instead, activated mTOR was responsible for BDNF's suppression of autophagic flux. shRNA against the autophagic machinery Atg7 or Atg5 prolonged the survival of neurons co-treated with BDNF and rapamycin, suggesting that suppression of mTOR in BDNF-treated cells resulted in excessive autophagy. Finally, acting as a physiological analog of rapamycin, IL-1β impaired BDNF signaling by way of inhibiting mTOR activation as follows: the cytokine induced caspase-independent neuronal death and accelerated autophagic flux in BDNF-treated cells. These findings reveal a novel mechanism of BDNF neuroprotection; BDNF not only prevents apoptosis through inhibiting caspase activation but also promotes neuron survival through modulation of autophagy. This protection mechanism is vulnerable under chronic inflammation, which deregulates autophagy through impairing mTOR signaling. These results may be relevant to age-related changes observed in neurodegenerative diseases.
哺乳动物雷帕霉素靶蛋白（mTOR）途径具有多种重要的生理功能，包括调节蛋白质合成、细胞生长、自噬和突触可塑性。mTOR 的激活对于脑源性神经营养因子（BDNF）的许多有益作用是必要的，包括树突翻译和海马体中的记忆形成。然而，目前 mTOR 在 BDNF 支持生存中的作用尚不清楚。我们报告说，mTOR 的激活对于原代大鼠海马神经元中 BDNF 依赖的生存是必要的，因为雷帕霉素对 mTOR 的抑制或下游分子 p70S6K 的遗传操作特异性地阻断了 BDNF 的挽救。然而，令人惊讶的是，BDNF 并没有通过上调 mTOR 依赖性蛋白质合成或通过 mTOR 依赖性抑制半胱天冬酶-3 的激活来促进神经元的存活。相反，激活的 mTOR 负责 BDNF 抑制自噬通量。针对自噬机制 Atg7 或 Atg5 的 shRNA 延长了同时用 BDNF 和雷帕霉素处理的神经元的存活时间，这表明 BDNF 处理细胞中 mTOR 的抑制导致了过度的自噬。最后，作为雷帕霉素的生理类似物，IL-1β 通过抑制 mTOR 激活来损害 BDNF 信号传导：细胞因子诱导了 caspase 非依赖性神经元死亡，并加速了 BDNF 处理细胞中的自噬通量。这些发现揭示了 BDNF 神经保护的一种新机制；BDNF 不仅通过抑制半胱天冬酶的激活来防止细胞凋亡，而且还通过调节自噬来促进神经元的存活。这种保护机制在慢性炎症下是脆弱的，慢性炎症通过损害 mTOR 信号传导来扰乱自噬。这些结果可能与神经退行性疾病中观察到的与年龄相关的变化有关。
