Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain
Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain
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DOI：
10.3233/jad-190656
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Yuan, Shauna H.
中科院分区：
文献类型：
--
作者：
Aulston, Brent;Liu, Qing;Yuan, Shauna H.
细胞外囊泡（EV）是由微囊泡和外泌体组成的一组异质的分泌颗粒，微囊泡通过细胞膜的出芽而释放，外泌体通过胞吐作用从多泡体分泌。EV货物由可以在细胞之间转移的各种蛋白质和核酸组成。重要的是，EV可能在病理上参与神经退行性疾病，如阿尔茨海默病（AD）。虽然已经发现源自AD神经元的EV在体外具有神经毒性，但对AD EV在体内的病理后果知之甚少。此外，尽管所有已知的家族性AD（fAD）突变都涉及淀粉样β蛋白前体（A β PP）或加工A β PP的机制，但微管相关蛋白tau的过度磷酸化似乎在fAD相关的神经变性中起关键作用，并且先前的报告表明EV可能在AD脑中传播tau病理。因此，我们假设fAD EV可能在fAD相关tau病理学的发展中具有机制性参与。为了测试这一点，我们从iPSC衍生的神经元培养物中分离EV，所述iPSC衍生的神经元培养物产生自携带A246E突变为早老素-1的fAD患者，并将这些EV立体定向注射到野生型C57BL/6小鼠的前额叶中。注射后5周，将小鼠安乐死并进行病理学评价。相对于PBS和非疾病对照EV注射组，用fAD EV注射的小鼠在多个位点显示增加的tau磷酸化。此外，注射fAD EV的海马CA1区神经元区域中的tau内含物比对照组显著更多。总的来说，这些发现将EV确定为fAD相关tau失调的潜在介质，并保证未来的研究以研究EV靶向治疗fAD的治疗潜力。
Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer's disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro, little is known about the pathological consequences of AD EVs in vivo. Furthermore, although all known familial AD (fAD) mutations involve either amyloid-beta protein precursor (A beta PP) or the machinery that processes A beta PP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD.