Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.
Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.
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DOI：
10.1016/j.jbc.2021.101159
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Strittmatter SM
中科院分区：
文献类型：
--
作者：
Nies SH;Takahashi H;Herber CS;Huttner A;Chase A;Strittmatter SM
在阿尔茨海默病 (AD) 中，病理性 tau 蛋白和淀粉样蛋白 (Aβ) 的沉积会导致突触丧失和认知能力下降。注射从人类 AD 大脑中提取的错误折叠的 tau 蛋白聚集体会导致 WT 小鼠大脑中 tau 蛋白病理学的模板化传播。在这里，我们评估了 Aβ 共病理学、删除已知可改变 AD 风险的基因座（Ptk2b、Grn 和 Tmem106b）以及注射 AD tau 提取物后使用 Fyn 激酶抑制剂对 tau 扩散进行药物干预的影响。在 APPswe/PSEN1ΔE9 转基因小鼠和 AppNL-F/NL-F 敲入小鼠的海马和皮层中，由人 tau 种子引发的 tau 内含物的密度和扩散没有改变。在用人类 tau 序列取代小鼠 tau 的小鼠中，模板匹配增强了神经炎 tau 负担。人 AD 脑 tau 富集制剂含有聚集的 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 病理在最初形成后通过很大程度上独立的机制传播。改变参与 Aβ 寡聚物诱导信号传导的 Fyn 和 Pyk2 (Ptk2b) 激酶的活性，或删除颗粒体蛋白前体和 TMEM106B 溶酶体蛋白的表达，不会改变体细胞 tau 包含负担或扩散。然而，将人 AD tau 种子注射到 WT 小鼠体内后，小鼠衰老对增加神经炎 tau 的积累有显着影响。这些研究完善了我们对能够调节 tau 扩散的因素的认识。
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.
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DOI：
10.1097/nen.0b013e318217a118
发表时间：
2011-05
影响因子：
3.2
作者：
DaRocha-Souto B;Scotton TC;Coma M;Serrano-Pozo A;Hashimoto T;Serenó L;Rodríguez M;Sánchez B;Hyman BT;Gómez-Isla T
通讯作者：
Gómez-Isla T
来自阿尔茨海默氏症大脑的独特病理tau构象体传播了非转基因小鼠的tau病理。
DOI：
10.1084/jem.20160833
发表时间：
2016-11-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guo JL;Narasimhan S;Changolkar L;He Z;Stieber A;Zhang B;Gathagan RJ;Iba M;McBride JD;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
影响因子：
16.6
作者：
Chakraborty P;Rivière G;Liu S;de Opakua AI;Dervişoğlu R;Hebestreit A;Andreas LB;Vorberg IM;Zweckstetter M
通讯作者：
Zweckstetter M
影响因子：
14
作者：
Brookmeyer, Ron;Johnson, Elizabeth;Arrighi, H. Michael
通讯作者：
Arrighi, H. Michael
影响因子：
12.7
作者：
Feng T;Lacrampe A;Hu F
通讯作者：
Hu F