A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer's disease.
A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer's disease.
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DOI：
10.1126/sciadv.abo7421
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发表时间：
2023-01-13
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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突触丢失与阿尔茨海默病（AD）的认知功能下降密切相关，但其潜在机制尚不清楚。Wnt信号传导缺陷导致AD中的突触功能障碍和丧失。一致的是，LRP 6受体的变体（LRP 6-瓦尔）具有减少的Wnt信号传导，与迟发性AD相关。然而，尚未检查LRP 6-瓦尔对健康和AD脑的影响。通过基因编辑产生的基因敲入小鼠，携带这种Lrp 6变体，发育正常。然而，Lrp 6-瓦尔小鼠的神经元对Wnt 7a没有反应，Wnt 7a是一种通过Frizzled-5受体促进突触组装的配体。Wnt 7a刺激低密度脂蛋白受体相关蛋白6（LRP 6）-卷曲蛋白-5复合物的形成，但如果LRP 6-瓦尔存在则不刺激。lrp 6-瓦尔小鼠表现出随着年龄增长而变得明显的结构和功能性突触缺陷。当与NL-G-FAD模型杂交时，Lrp 6-瓦尔小鼠在斑块周围呈现加剧的突触损失。我们的研究结果揭示了Lrp 6-瓦尔在衰老和AD过程中突触脆弱性中的一个先前未被识别的作用。Lrp 6-瓦尔通过抑制Wnt受体复合物的形成诱导衰老和阿尔茨海默病中的突触丧失。
Synapse loss strongly correlates with cognitive decline in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Deficient Wnt signaling contributes to synapse dysfunction and loss in AD. Consistently, a variant of the LRP6 receptor, (LRP6-Val), with reduced Wnt signaling, is linked to late-onset AD. However, the impact of LRP6-Val on the healthy and AD brain has not been examined. Knock-in mice, generated by gene editing, carrying this Lrp6 variant develop normally. However, neurons from Lrp6-val mice do not respond to Wnt7a, a ligand that promotes synaptic assembly through the Frizzled-5 receptor. Wnt7a stimulates the formation of the low-density lipoprotein receptor-related protein 6 (LRP6)–Frizzled-5 complex but not if LRP6-Val is present. Lrp6-val mice exhibit structural and functional synaptic defects that become pronounced with age. Lrp6-val mice present exacerbated synapse loss around plaques when crossed to the NL-G-F AD model. Our findings uncover a previously unidentified role for Lrp6-val in synapse vulnerability during aging and AD. Lrp6-val induces synapse loss in aging and in Alzheimer’s disease by inhibiting the formation of the Wnt receptor complex.
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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
影响因子：
11.8
作者：
Chen, Shuo;Bubeck, Doryen;MacDonald, Bryan T.;Liang, Wen-Xue;Mao, Jian-Hua;Malinauskas, Tomas;Llorca, Oscar;Aricescu, A. Radu;Siebold, Christian;He, Xi;Jones, E. Yvonne
通讯作者：
Jones, E. Yvonne
影响因子：
4.8
作者：
Bourhis, Eric;Tam, Christine;Hannoush, Rami N.
通讯作者：
Hannoush, Rami N.
影响因子：
64.5
作者：
Hsieh, JC;Lee, L;Holdener, BC
通讯作者：
Holdener, BC
影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans