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Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.jbc.2021.101159
Sarah Helena Nies 1 , Hideyuki Takahashi 2 , Charlotte S Herber 2 , Anita Huttner 3 , Alison Chase 2 , Stephen M Strittmatter 2
Affiliation  

In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and AppNL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer-induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.

中文翻译:

老化和模板匹配增强了阿尔茨海默 tau 种子的传播,而淀粉样蛋白-β 的影响有限。

在阿尔茨海默病 (AD) 中,病理性 tau 和淀粉样蛋白-β (Aβ) 的沉积会导致突触丧失和认知能力下降。从人类 AD 大脑中提取的错误折叠 tau 聚集体的注射推动了 tau 病理学在 WT 小鼠大脑中的模板化传播。在这里,我们评估了 Aβ 共病理学、删除已知会改变 AD 风险的位点(Ptk2b、Grn 和 Tmem106b)以及在注射 AD tau 提取物后用 Fyn 激酶抑制剂进行药物干预对 tau 扩散的影响。在 APPswe/PSEN1ΔE9 转基因和 AppNL-F/NL-F 敲入小鼠的海马和皮质中,人类 tau 种子引发的 tau 包涵体的密度和扩散没有改变。在人类 tau 序列取代小鼠 tau 的小鼠中,模板匹配增强了神经炎性 tau 负担。人 AD 脑富含 tau 的制剂含有聚集的 Aβ,Aβ共注射导致突变AD模型小鼠中Aβ聚集体的重新分布。注射诱导的 Aβ 表型在空间上与 tau 积累不同,可以通过消耗 tau 提取物中的 Aβ 来改善。这些数据表明,Aβ 和 tau 病理在其初始形成后通过很大程度上独立的机制传播。改变参与 Aβ-寡聚体诱导的信号传导的 Fyn 和 Pyk2 (Ptk2b) 激酶的活性,或删除颗粒蛋白前体和 TMEM106B 溶酶体蛋白的表达,并没有改变体细胞 tau 包涵体的负担或扩散。然而,在将人 AD tau 种子注射到 WT 小鼠中后,小鼠衰老对增加神经炎性 tau 的积累具有显着影响。这些研究完善了我们对能够调节 tau 扩散的因素的认识。
更新日期:2021-09-01
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