TAPPing into the potential of inducible tau/APP transgenic mice.
TAPPing into the potential of inducible tau/APP transgenic mice.
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挖掘可诱导 tau/APP 转基因小鼠的潜力。
DOI：
10.1111/nan.12791
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发表时间：
2022
影响因子：
5
通讯作者：
Lewis,Jada
中科院分区：
文献类型：
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作者：
Xu,Guilian;Ulm,BrittanyS;Howard,John;Fromholt,SusanE;Lu,Qing;Lee,BrianBenedict;Walker,Ariel;Borchelt,DavidR;Lewis,Jada
目的我们对阿尔茨海默病中淀粉样变和牛头病之间的病理相互作用的了解尚不完整。我们试图确定淀粉样变和牛头病的相对时间是否对淀粉样蛋白增强的牛头病至关重要。方法利用多西环素抑制转基因系统，将诱导型tau模型与两个β -淀粉样蛋白模型杂交，以调节淀粉样变背景下人类tau表达的时间和持续时间，然后评估tau病，淀粉样变和胶质瘤。结果我们将可诱导的rTg4510 tau与APPswe/PS1dE9 [Line 85 (L85)]小鼠结合，研究了Aβ与淀粉样变性不同阶段tau病变之间的相互作用。当我们最初抑制突变型人类tau蛋白表达14-15个月，随后诱导tau蛋白表达6个月时，rTg4510/L85小鼠出现了严重的淀粉样变性并出现了严重的tau病变，而rTg4510小鼠则没有。当我们在另一组rTg4510/L85和rTg4510小鼠中抑制突变tau 7个月，然后诱导其随后6个月的表达时，只有rTg4510/L85小鼠表现出强烈的tau病变。最后，我们将rTg4510小鼠与tet调控的APPswe/ind [Line 107 (L107)]小鼠杂交，使用多西环素初始抑制这两种转基因1个月，然后诱导表达5个月，以模拟早期淀粉样变性。与rTg4510相比，rTg4510/L107小鼠迅速发生淀粉样变性，并伴有严重的牛头病。这些数据表明，年轻大脑中新形成的Aβ沉积物和老年大脑中成熟的沉积物都加剧了tau蛋白的错误折叠。这些模型的精细使用和重新利用为探索衰老，淀粉样蛋白和tau病的交叉点以及测试干扰淀粉样蛋白级联的干预措施提供了新的工具。
AimsOur understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid‐enhanced tauopathy.MethodsWe crossed an inducible tauopathy model with two β‐amyloid models utilising the doxycycline‐repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis.ResultsWe combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14–15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet‐regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy.ConclusionsThese data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.