Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain.
Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain.
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DOI：
10.3390/jcm10173931
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发表时间：
2021-08-31
影响因子：
3.9
通讯作者：
Granholm AC
中科院分区：
文献类型：
--
作者：
Ledreux A;Thomas S;Hamlett ED;Trautman C;Gilmore A;Rickman Hager E;Paredes DA;Margittai M;Fortea J;Granholm AC
唐氏综合症 (DS) 患者在年轻时就表现出阿尔茨海默病 (AD) 病理学，包括淀粉样蛋白斑和神经原纤维缠结 (NFT)。 Tau 病理学可以通过细胞外囊泡（例如外泌体）传播。 DS 患者的神经元来源的小细胞外囊泡 (NDEV) 在早期就含有 p-Tau。该研究的目的是调查从 DS 患者血液中分离出的 NDEV 是否可以在野生型小鼠的大脑中传播 Tau 病理学。我们从 DS-AD 患者和对照组的血浆中纯化了 NDEV，并通过立体定位手术将少量 NDEV 注射到成年野生型小鼠的背侧海马体中。接种感受态 Tau 构象异构体在体外从 DS-AD NDEV 扩增，但未从对照 NDEV 扩增。注射后 1 个月或 4 个月，我们检查了小鼠大脑中的 Tau 病理学。我们发现，与注射年龄匹配的对照 NDEV 相比，注射 DS-AD NDEV 的小鼠海马中有丰富的 p-Tau 免疫染色。神经元和神经胶质标记物的双重标记表明，p-Tau 染色主要存在于神经元中，少量存在于神经胶质细胞中，并且 p-Tau 免疫染色沿着胼胝体和海马的中横向轴扩散。这些研究表明，来自 DS-AD 患者的 NDEV 表现出 Tau 播种能力，并产生缠结状细胞内包涵体。
Individuals with Down syndrome (DS) exhibit Alzheimer’s disease (AD) pathology at a young age, including amyloid plaques and neurofibrillary tangles (NFTs). Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions.
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