Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.
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DOI：
10.1186/s13024-022-00562-8
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发表时间：
2022-09-02
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，表现为Aβ和tau蛋白的连续性脑病理改变，具有年龄依赖性发病。小胶质细胞免疫受体TREM 2的变异与散发性阿尔茨海默病（AD）发病风险增加相关。虽然最近的研究表明TREM 2功能障碍可以加重tau病理，但tau病理的TREM 2依赖性调节的潜在机制仍然难以捉摸。在这里，我们通过将AAV-P301 L tau注射到MEC中来表征野生型（WT）和Trem 2敲除（KO）小鼠中从内侧内嗅皮层（MEC）向海马扩散的进行性tau的差异，并将海马tau组织病理学的变化与空间和恐惧记忆相关联。我们还使用微流体分散测定比较了培养的小胶质细胞和神经元之间的神经元内分散的效果，分析了摄取后小胶质细胞tau运输的差异，并定量了纯化的WT和Trem 2 KO外泌体的外泌体tau分泌和致病性。小鼠中的Trem 2缺失（Trem 2 KO）可以增强tau从内侧内嗅皮层（MEC）向海马的扩散，这与受损的突触功能和记忆行为相一致。小胶质细胞中的Trem 2缺失增强了tau在体外在微流体室中培养的神经元层之间的神经元内分散，并且外泌体抑制剂的存在可以显著减少来自tau负载的小胶质细胞的外泌体和细胞外培养基中的tau。虽然小胶质细胞Trem 2缺失对tau摄取没有影响，但Trem 2缺失增强了内化后分布到内体和细胞外泌体前区室。Trem 2缺失对外泌体大小几乎没有影响，然而，蛋白质组学分析表明，Trem 2缺失可以调节与外泌体诱导相关的tau和LPS/ATP处理条件下小胶质细胞蛋白质组学景观的变化。此外，与来自WT小胶质细胞的外泌体相比，来自Trem 2 KO小胶质细胞的外泌体显示出升高的tau水平，并且在tau FRET报告细胞系中具有增强的tau接种能力。总之，我们的结果揭示了Trem 2在抑制外泌体tau致病性中的作用，并证明了Trem 2缺失可以增强tau通过小胶质细胞外泌体的运输、分布和播种。在线版本包含补充材料，可通过10.1186/s13024-022-00562-8获得。
Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer’s disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive. Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes. Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia. Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes. The online version contains supplementary material available at 10.1186/s13024-022-00562-8.
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影响因子：
4.3
作者：
Hansson O;Grothe MJ;Strandberg TO;Ohlsson T;Hägerström D;Jögi J;Smith R;Schöll M
通讯作者：
Schöll M
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
64.5
作者：
BEACH, ME;HAWKINS, RD;MAYFORD, M
通讯作者：
MAYFORD, M
影响因子：
14.5
作者：
de Gerando, Anastasie Mate;d'Orange, Marie;Cambon, Karine
通讯作者：
Cambon, Karine