Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.
Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.
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DOI：
10.1016/j.cub.2016.07.024
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发表时间：
2016-10-10
期刊：
影响因子：
9.2
通讯作者：
Salinas, Patricia C.
中科院分区：
文献类型：
--
作者：
Marzo, Aude;Galli, Soledad;Lopes, Douglas;McLeod, Faye;Podpolny, Marina;Segovia-Roldan, Margarita;Ciani, Lorenza;Purro, Silvia;Cacucci, Francesca;Gibb, Alasdair;Salinas, Patricia C.
突触变性发生在神经退行性疾病的早期，并与阿尔茨海默病（AD）的认知能力下降密切相关。触发突触脆弱性的分子机制和那些促进突触再生后，大量的突触故障仍然知之甚少。越来越多的证据表明Wnt信号传导的缺陷与AD之间存在联系。分泌的Wnt拮抗剂Dickkopf-1（Dkk 1）在AD中升高，导致淀粉样蛋白-β介导的突触失败。然而，Dkk 1在回路水平的影响和突触解体的机制尚未被探索。使用转基因小鼠模型，诱导表达Dkk 1在海马，我们证明，Dkk 1触发突触丢失，损害长时程增强，增强长期抑郁症，并诱导学习和记忆缺陷。我们解释了Dkk 1诱导的突触丢失的机制，因为它可以通过Gsk 3和RhoA-Rock通路的联合抑制来预防。值得注意的是，在突触连接丧失后，通过停止Dkk 1表达重新激活Wnt通路完全恢复突触数量、突触可塑性和长期记忆。这些发现证明了成年神经元再生功能回路的显着能力，并强调Wnt信号传导是突触变性后神经元回路恢复的靶向途径。Wnt信号传导是成年海马体中突触完整性所必需的Dkk 1诱导突触丧失和突触可塑性和长期记忆的缺陷Dkk 1通过激活Gsk 3和Rock途径来分解突触突触丧失和记忆缺陷通过Wnt途径的再激活是可逆的Wnt信号传导的缺陷与阿尔茨海默病有关。Marzo等人阐明Wnt拮抗剂Dkk 1在成年海马中的影响，显示突触损失和突触可塑性和长期记忆的缺陷。他们还揭示了Dkk 1表达的停止诱导突触再生和长期记忆的恢复。
Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer’s disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration. Wnt signaling is required for synapse integrity in the adult hippocampus Dkk1 induces synapse loss and deficits in synaptic plasticity and long-term memory Dkk1 disassembles synapses by activating the Gsk3 and Rock pathways Synapse loss and memory defects are reversible by reactivation of the Wnt pathway Deficiency in Wnt signaling has been implicated in Alzheimer’s disease. Marzo et al. elucidate the impact of the Wnt antagonist Dkk1 in the adult hippocampus, showing synapse loss and defects in synaptic plasticity and long-term memory. They also reveal that cessation of Dkk1 expression induces synapse regeneration and recovery of long-term memory.
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影响因子：
16.6
作者：
Ciani L;Marzo A;Boyle K;Stamatakou E;Lopes DM;Anane D;McLeod F;Rosso SB;Gibb A;Salinas PC
通讯作者：
Salinas PC
DOI：
10.1073/pnas.0500195102
发表时间：
2005-03-08
影响因子：
11.1
作者：
De Rosa, R;Garcia, AA;Cattaneo, A
通讯作者：
Cattaneo, A
DOI：
10.1073/pnas.1008200107
发表时间：
2010-09-21
影响因子：
11.1
作者：
Ge, Yuan;Dong, Zhifang;Wang, Yu Tian
通讯作者：
Wang, Yu Tian
影响因子：
5.7
作者：
Budnik V;Salinas PC
通讯作者：
Salinas PC
影响因子：
10.5
作者：
Caneparo, Luca;Huang, Ya-Lin;Houart, Corinne
通讯作者：
Houart, Corinne