Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction.
Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction.
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DOI：
10.1172/jci.insight.152012
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发表时间：
2022-01-11
期刊：
影响因子：
8
通讯作者：
Miller TM
中科院分区：
文献类型：
--
作者：
Ezerskiy LA;Schoch KM;Sato C;Beltcheva M;Horie K;Rigo F;Martynowicz R;Karch CM;Bateman RJ;Miller TM
tau蛋白及其亚型与几种神经退行性疾病相关，其中许多疾病的特征在于4-重复（4 R）tau亚型的更多沉积;然而，4 R tau在疾病发病机制中的作用仍不清楚。我们创建了改变3R与4 R tau的比率的反义寡核苷酸（ASO），以研究特定tau亚型在疾病中的作用。先前显示在表达人tau（表达hTau）的小鼠中优先表达4 R tau增加癫痫发作严重性和磷酸化tau沉积，而没有神经元或突触损失。在这项研究中，我们观察到4 R tau在反应性星形胶质细胞内的强烈共定位，以及在hTau小鼠中3R至4 R tau剪接阿索治疗后泛反应性和神经毒性基因的表达增加。在原代星形胶质细胞中增加4 R tau水平引起了类似的反应，包括神经毒性遗传特征和降低的稳态功能，这在人类诱导多能干细胞衍生的（iPSC衍生的）星形胶质细胞中复制，该星形胶质细胞具有表现出更大的4 R tau突变。与表达4 R tau的人iPSC衍生的星形胶质细胞一起培养的健康神经元表现出更高的放电频率和超同步性，这可以通过降低tau表达来防止。这些发现支持星形胶质细胞4 R tau介导反应性和功能障碍的潜在新途径，并表明针对4 R tau的星形胶质细胞靶向治疗可能减轻神经退行性疾病进展。
The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau–expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes and increased expression of pan-reactive and neurotoxic genes following 3R to 4R tau splicing ASO treatment in hTau mice. Increasing 4R tau levels in primary astrocytes provoked a similar response, including a neurotoxic genetic profile and diminished homeostatic function, which was replicated in human induced pluripotent stem cell–derived (iPSC-derived) astrocytes harboring a mutation that exhibits greater 4R tau. Healthy neurons cultured with 4R tau–expressing human iPSC–derived astrocytes exhibited a higher firing frequency and hypersynchrony, which could be prevented by lowering tau expression. These findings support a potentially novel pathway by which astrocytic 4R tau mediates reactivity and dysfunction and suggest that astrocyte-targeted therapeutics against 4R tau may mitigate neurodegenerative disease progression.
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影响因子：
8.9
作者：
Josephs KA
通讯作者：
Josephs KA
影响因子：
5.3
作者：
DeVos, Sarah L.;Goncharoff, Dustin K.;Miller, Timothy M.
通讯作者：
Miller, Timothy M.
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.3791/562
发表时间：
2007-01-01
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Hilgenberg, Lutz G W;Smith, Martin A
通讯作者：
Smith, Martin A
星形胶质细胞是Aβ诱导的神经毒性和TAU磷酸化的重要介体。
影响因子：
9
作者：
通讯作者：
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