Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

Dejanovic Borislav; Huntley Melanie A.; De Maziere Ann; Meilandt William J.; Wu Tiffany; Srinivasan Karpagam; Jiang Zhiyu; Gandham Vineela; Friedman Brad A.; Hai Ngu; Foreman Oded; Carano Richard A. D.; Chih Ben; Klumperman Judith; Bakalarski Corey; Hanson Jesse E.; Sheng Morgan

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Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

机译：C1Q抗体胁迫和Tau诱导突触损失拯救突触蛋白质组的变化

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Synapse loss and Tau pathology are hallmarks of Alzheimer's disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent alterations in synapses prior to overt neurodegeneration. Multiple proteins and pathways were altered in Tau-P301S PSDs, including depletion of a set of GTPase- regulatory proteins that leads to actin cytoskeletal defects and loss of dendritic spines. Furthermore, we found striking accumulation of complement C1q in the PSDs of Tau-P301S mice and AD patients. At synapses, C1q decorated perisynaptic membranes, accumulated in correlation with phospho-Tau, and was associated with augmented microglial engulfment of synapses and decline of synapse density. A C1q-blocking antibody inhibited microglial synapse removal in cultured neurons and in Tau-P301S mice, rescuing synapse density. Thus, inhibiting complement-mediated synapse removal by microglia could be a potential therapeutic target for Tauassociated neurodegeneration.

机译：Synapse损失和Tau病理是阿尔茨海默病（AD）和其他部落观的标志，但Tau病理如何导致突触损失尚不清楚。我们在TAU-P301S转基因小鼠中使用了对突触后密度（PSDS）的非偏见的蛋白质组学分析，以鉴定公开神经变性之前的突触依赖性改变。在TAU-P301S PSD中改变了多种蛋白质和途径，包括耗尽一组GTP酶调节蛋白，导致肌动蛋白骨骼缺陷和树突刺的丧失。此外，我们发现在TAU-P301S小鼠和AD患者的PSD中发现了补体C1Q的积累。在突触中，C1Q装饰的蠕虫膜，累积在与磷酸盐相关的相关性，并且与突触密度的突触突触的增强显微吞噬有关。 C1Q阻断抗体抑制培养的神经元和Tau-P301S小鼠中的小胶质突触去除，拯救突触密度。因此，抑制微胶质细胞的补体介导的突触去除可能是TAUAseCiated神经变性的潜在治疗靶标。

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《Neuron》 |2018年第6期|共22页
作者
Dejanovic Borislav; Huntley Melanie A.; De Maziere Ann; Meilandt William J.; Wu Tiffany; Srinivasan Karpagam; Jiang Zhiyu; Gandham Vineela; Friedman Brad A.; Hai Ngu; Foreman Oded; Carano Richard A. D.; Chih Ben; Klumperman Judith; Bakalarski Corey; Hanson Jesse E.; Sheng Morgan;
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Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Univ Utrecht Univ Med Ctr Utrecht Ctr Mol Med Sect Cell Biol NL-3584 CX Utrecht Netherlands;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Biomed Imaging San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Pathol San Francisco CA 94080 USA;

Genentech Inc Dept Pathol San Francisco CA 94080 USA;

Genentech Inc Dept Biomed Imaging San Francisco CA 94080 USA;

Genentech Inc Dept Biochem &

Cellular Pharmacol San Francisco CA 94080 USA;

Univ Utrecht Univ Med Ctr Utrecht Ctr Mol Med Sect Cell Biol NL-3584 CX Utrecht Netherlands;

Genentech Inc Dept Bioinformat &

Computat Biol San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

Genentech Inc Dept Neurosci San Francisco CA 94080 USA;

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正文语种 eng
中图分类神经病学;
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专利

1. Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies [J] . Dejanovic Borislav, Huntley Melanie A., De Maziere Ann, Neuron . 2018,第6期

机译：C1Q抗体胁迫和Tau诱导突触损失拯救突触蛋白质组的变化
2. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy [J] . Crescenzi Rachelle, DeBrosse Catherine, Nanga Ravi Prakash Reddy, NeuroImage . 2014,第Null期

机译：在tauopathy小鼠模型中谷氨酸损失的体内测量与突触损失有关
3. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy [J] . Crescenzi Rachelle, DeBrosse Catherine, Nanga Ravi Prakash Reddy, NeuroImage . 2014,第Null期

机译：体内谷氨酸损失的测量与施特病小鼠模型中的突触损失有关
4. Synapse Loss, Synaptic Plasticity and the Postsynaptic Density [C] . Morgan Shen Colloque me?decine et recherche . 2008

机译：突触损失，突触可塑性和突触后密度
5. A novel approach to control and regulate the classical complement pathway: Highly specific inhibition of C1q globular head binding to human IgG using an engineered single chain antibody variable fragment; recruiting C1q to HER2 /neu positive cells using truncated bispecific antibodies [D] . Hwang, Hee Young 2007

机译：一种控制和调节经典补体途径的新方法：使用工程化的单链抗体可变片段高度特异性地抑制C1q球头与人IgG的结合；使用截短的双特异性抗体将C1q募集到HER2 / neu阳性细胞
6. Rescue of tau-induced synaptic transmission pathology by paclitaxel [O] . Hadas Erez, Or A. Shemesh, Micha E. Spira 2014

机译：紫杉醇拯救tau诱导的突触传递病理
7. Rescue of tau-induced synaptic transmission pathology by paclitaxel [O] . Hdas eErez, Or A Shemesh, Micha E. Spira 2014

机译：紫杉醇拯救tau诱导的突触传递病理学

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

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