Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice
Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice
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DOI：
10.3233/jad-160371
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Gotz, Jurgen
中科院分区：
文献类型：
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作者：
Baker, Sian;Polanco, Juan Carlos;Gotz, Jurgen
在阿尔茨海默氏病中，神经元缠结的分布，一种由磷酸化形式的tau蛋白组成的组织学标志，在解剖学连接的大脑区域中遵循不同的模式。tau病理学的严重程度与疾病进展之间的充分记录的相关性暗示了tau的朊病毒样播种和扩散机制。在实验上，这已经通过注射从转基因小鼠或患有tau蛋白病（包括AD）的患者的脑中分离的蛋白质裂解物而在转基因小鼠中得到解决，所述蛋白质裂解物显示出像种子一样的行为，加速了易感小鼠中的tau蛋白病和缠结形成。更具体地说，体内数据表明，来自携带tau的P301S突变的小鼠的脑裂解物在注射到人野生型tau转基因ALZ 17小鼠的脑中时可以引起蛋白质聚集。在这里，我们比较了来自野生型和人P301L tau转基因rTg4510小鼠脑的裂解物和富含外来体（EV）的细胞外囊泡的接种潜力。我们表明，转基因EV引起tau蛋白磷酸化和可溶性寡聚体形成的方式与脑裂解物中的自由可用蛋白质相当，这是形成成熟蛋白质聚集体的先决条件。
In Alzheimer's disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates.