TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.
TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.
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DOI：
10.1016/j.neuron.2017.05.037
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发表时间：
2017-07-19
期刊：
影响因子：
16.2
通讯作者：
Rajendran L
中科院分区：
文献类型：
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作者：
Paolicelli RC;Jawaid A;Henstridge CM;Valeri A;Merlini M;Robinson JL;Lee EB;Rose J;Appel S;Lee VM;Trojanowski JQ;Spires-Jones T;Schulz PE;Rajendran L
小胶质细胞协调中枢神经系统中的各种功能，从消除突触连接到通过监测神经元功能来维持大脑稳态，以及在整个生命周期中清除蛋白质聚集体。在这里，我们研究了是否增加的小胶质细胞吞噬活性，清除淀粉样蛋白也可以导致病理性突触丢失。我们鉴定了TDP-43，一种由Tardbp基因编码的DNA-RNA结合蛋白，作为小胶质细胞吞噬作用的强调节剂。在小胶质细胞中缺乏TDP-43的小鼠在阿尔茨海默病（AD）模型中表现出淀粉样蛋白负荷减少，但同时显示出急剧的突触丧失，即使在没有淀粉样蛋白的情况下。TDP-43病理学病例的临床检查显示，与年龄匹配的健康对照相比，AD的患病率显著降低，淀粉样蛋白病理学降低，证实了我们的实验结果。总的来说，我们的数据表明，功能失调的小胶质细胞可能在神经退行性疾病的发病机制中发挥致病作用，关键性地调节认知能力下降的早期阶段。TDP-43调节小胶质细胞吞噬作用和Aβ的清除小胶质细胞TDP-43的消耗导致增强的突触丧失小胶质细胞TDP-43的消耗促进AD小鼠模型中的淀粉样蛋白清除TDP-43病理学与死后脑中较低的淀粉样蛋白沉积相关Paolicelli et al.显示TDP-43是小胶质细胞吞噬作用调节剂。他们发现，缺乏小胶质细胞TDP-43的小鼠显示淀粉样蛋白清除增强，但也有显著的突触丢失。他们还表明，TDP-43病理学与人脑中淀粉样蛋白负荷减少有关。
Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer’s disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline. TDP-43 regulates microglial phagocytosis and clearance of Aβ Depletion of microglial TDP-43 results in enhanced synapse loss Depletion of microglial TDP-43 promotes amyloid clearance in a mouse model of AD TDP-43 pathology is associated with lower amyloid deposition in post-mortem brains Paolicelli et al. show that TDP-43 is a regulator of microglial phagocytosis. They found that mice lacking microglial TDP-43 display enhanced amyloid clearance but also significant synapse loss. They also show that TDP-43 pathology is associated with reduced amyloid burden in human brains.
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影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
小胶质细胞在发育和晚年中枢神经系统病理学中发挥着关键作用。
影响因子：
12.7
作者：
Derecki NC;Katzmarski N;Kipnis J;Meyer-Luehmann M
通讯作者：
Meyer-Luehmann M
DOI：
10.1007/978-1-62703-520-0_4
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Deierborg, Tomas
通讯作者：
Deierborg, Tomas
影响因子：
15.9
作者：
Igaz, Lionel M.;Kwong, Linda K.;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
影响因子：
3.5
作者：
Diaper DC;Adachi Y;Sutcliffe B;Humphrey DM;Elliott CJ;Stepto A;Ludlow ZN;Vanden Broeck L;Callaerts P;Dermaut B;Al-Chalabi A;Shaw CE;Robinson IM;Hirth F
通讯作者：
Hirth F