Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.
Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.
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DOI：
10.1016/j.neuron.2020.12.016
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发表时间：
2021-03-03
期刊：
影响因子：
16.2
通讯作者：
Verstreken P
中科院分区：
文献类型：
--
作者：
Largo-Barrientos P;Apóstolo N;Creemers E;Callaerts-Vegh Z;Swerts J;Davies C;McInnes J;Wierda K;De Strooper B;Spires-Jones T;de Wit J;Uytterhoeven V;Verstreken P
Tau是神经变性的主要驱动因素，与20多种疾病有关。Tauopathies的特征在于突触丢失和神经炎症，但尚不清楚这些病理事件是否存在因果关系。Tau结合突触囊泡上的突触回蛋白-3。在这里，我们干扰了这一功能，以确定致病性Tau在突触前末梢的作用。我们发现，突触回蛋白-3的杂合敲除在小鼠中是良性的，但强烈地挽救了突变体Tau诱导的长期突触可塑性和工作记忆缺陷。它还显著挽救了由突变体Tau引起的突触前和突触后损失。然而，当我们去除突触回蛋白-3的一个等位基因的表达时，Tau诱导的神经炎症仍然明显上调。因此，神经炎症不足以引起突触损失，并且这些过程是响应于突变体Tau而单独诱导的。此外，突变Tau引起的突触前缺陷足以驱动认知任务的缺陷。降低突触回蛋白-3水平在小鼠中是良性的降低突触回蛋白-3表达挽救了Tau诱导的突触可塑性和工作记忆缺陷Tau诱导的突触丢失可以在神经炎症的存在下挽救Tau蛋白与多种脑疾病（包括阿尔茨海默病）有关。在病理条件下，Tau在突触前末端与突触囊泡相关蛋白Synaptogyrin-3相互作用。在这份报告中，Largo-Barrientos et al.显示降低突触回蛋白-3的表达防止Tau诱导的突触丧失和认知下降，而神经炎症仍然显著上调。
Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role of pathogenic Tau at pre-synaptic terminals. We show that heterozygous knockout of synaptogyrin-3 is benign in mice but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. It also significantly rescues the pre- and post-synaptic loss caused by mutant Tau. However, Tau-induced neuroinflammation remains clearly upregulated when we remove the expression of one allele of synaptogyrin-3. Hence neuroinflammation is not sufficient to cause synaptic loss, and these processes are separately induced in response to mutant Tau. In addition, the pre-synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks. Tau accrues at Synaptogyrin-3-positive synapses in a tauopathy mouse model and AD patient brains Lowering Synaptogyrin-3 levels is benign in mice Lowering Synaptogyrin-3 expression rescues Tau-induced synaptic plasticity and working memory defects Tau-induced synaptic loss can be rescued in the presence of neuroinflammation Tau protein is implicated in multiple brain disorders (including Alzheimer’s disease). In pathological conditions, Tau interacts with the synaptic vesicle-associated protein Synaptogyrin-3 at pre-synaptic terminals. In this report, Largo-Barrientos et al. show that lowering the expression of Synaptogyrin-3 prevents Tau-induced synaptic loss and cognitive decline, while neuroinflammation remains conspicuously upregulated.
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DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
8.8
作者：
Jackson JS;Witton J;Johnson JD;Ahmed Z;Ward M;Randall AD;Hutton ML;Isaac JT;O'Neill MJ;Ashby MC
通讯作者：
Ashby MC
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
56.9
作者：
Lledo, PM;Zhang, XY;Nicoll, RA
通讯作者：
Nicoll, RA
影响因子：
4.2
作者：
Gilley, Jonathan;Ando, Kunie;Coleman, Michael P.
通讯作者：
Coleman, Michael P.