Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice.
Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice.
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DOI：
10.1186/s40478-023-01661-3
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发表时间：
2023-10-19
影响因子：
7.1
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中科院分区：
文献类型：
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Tau微管蛋白激酶-1（TTBK 1）是一种神经元特异性tau激酶，在内嗅皮质和海马区高度表达，在阿尔茨海默病（AD）中早期tau病理演变。与对照组相比，AD患者大脑皮层组织中TTBK 1的蛋白表达水平升高。因此，我们假设基于靶向Ttbk 1的反义寡核苷酸（阿索）可以防止磷酸化tau的积累，从而延迟AD中tau病理学的发展。在这里，我们表明，在体内管理的阿索靶向小鼠Ttbk 1（ASO-Ttbk 1）特异性抑制Ttbk 1的表达，而不影响Ttbk 2表达的PS19 tau转基因小鼠的颞叶皮层。在给药后8周，PS19小鼠中ASO-Ttbk 1的中枢给药显著降低了与AD相关的代表性磷酸化tau表位的表达水平，包括从海马组织分离的肌氨酰可溶性和不溶性级分中的pT 231、pT 181和pS396（如通过ELISA测定的）和可溶性级分中的pS422（如通过蛋白质印迹测定的）。免疫荧光显示ASO-Ttbk 1显著降低PS19小鼠齿状回苔藓纤维区pS422磷酸化tau蛋白的强度。颞叶皮质组织的RNA序列分析显示，在ASO-Ttbk 1处理的PS19小鼠中，干扰素-γ和补体途径显著富集，抗原呈递分子（Cd 86、Cd 74和H2-Aa）表达增加，表明其对小胶质细胞表型的潜在影响，尽管不存在神经毒性作用。这些数据表明，TTBK 1是一个有吸引力的治疗目标，以抑制TTBK 1，而不损害TTBK 2的表达和病理性tau磷酸化在AD的早期阶段。在线版本包含补充材料，可通过10.1186/s40478-023-01661-3获得。
Tau tubulin kinase-1 (TTBK1), a neuron-specific tau kinase, is highly expressed in the entorhinal cortex and hippocampal regions, where early tau pathology evolves in Alzheimer’s disease (AD). The protein expression level of TTBK1 is elevated in the cortex brain tissues with AD patients compared to the control subjects. We therefore hypothesized that antisense oligonucleotide (ASO) based targeting Ttbk1 could prevent the accumulation of phosphorylated tau, thereby delaying the development of tau pathology in AD. Here we show that in vivo administration of ASO targeting mouse Ttbk1 (ASO-Ttbk1) specifically suppressed the expression of Ttbk1 without affecting Ttbk2 expression in the temporal cortex of PS19 tau transgenic mice. Central administration of ASO-Ttbk1 in PS19 mice significantly reduced the expression level of representative phosphor-tau epitopes relevant to AD at 8 weeks post-dose, including pT231, pT181, and pS396 in the sarkosyl soluble and insoluble fractions isolated from hippocampal tissues as determined by ELISA and pS422 in soluble fractions as determined by western blotting. Immunofluorescence demonstrated that ASO-Ttbk1 significantly reduced pS422 phosphorylated tau intensity in mossy fibers region of the dentate gyrus in PS19 mice. RNA-sequence analysis of the temporal cortex tissue revealed significant enrichment of interferon-gamma and complement pathways and increased expression of antigen presenting molecules (Cd86, Cd74, and H2-Aa) in PS19 mice treated with ASO-Ttbk1, suggesting its potential effect on microglial phenotype although neurotoxic effect was absent. These data suggest that TTBK1 is an attractive therapeutic target to suppress TTBK1 without compromising TTBK2 expression and pathological tau phosphorylation in the early stages of AD. The online version contains supplementary material available at 10.1186/s40478-023-01661-3.
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影响因子：
4.7
作者：
Sato, Shinji;Cerny, Ronald L.;Ikezu, Tsuneya
通讯作者：
Ikezu, Tsuneya
影响因子：
7.1
作者：
Ikezu, Seiko;Ingraham Dixie, Kaitlin L.;Ikezu, Tsuneya
通讯作者：
Ikezu, Tsuneya
影响因子：
2.5
作者：
Kohnken, R;Buerger, K;Hampel, H
通讯作者：
Hampel, H
影响因子：
64.8
作者：
Shi Y;Yamada K;Liddelow SA;Smith ST;Zhao L;Luo W;Tsai RM;Spina S;Grinberg LT;Rojas JC;Gallardo G;Wang K;Roh J;Robinson G;Finn MB;Jiang H;Sullivan PM;Baufeld C;Wood MW;Sutphen C;McCue L;Xiong C;Del-Aguila JL;Morris JC;Cruchaga C;Alzheimer’s Disease Neuroimaging Initiative;Fagan AM;Miller BL;Boxer AL;Seeley WW;Butovsky O;Barres BA;Paul SM;Holtzman DM
通讯作者：
Holtzman DM
影响因子：
4.7
作者：
Sahara, N;Lewis, J;Yen, SH
通讯作者：
Yen, SH