βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease
βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease
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DOI：
10.1093/cercor/bhx260
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发表时间：
2018-11-01
期刊：
影响因子：
3.7
通讯作者：
Braudeau, Jerome
中科院分区：
文献类型：
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作者：
Audrain, Mickael;Souchet, Benoit;Braudeau, Jerome
阿尔茨海默病(AD)的治疗仍然具有挑战性，需要对AD进展有更深入的了解。特别是，淀粉样蛋白前体(APP)处理和Tau病理发展之间的联系仍然知之甚少。越来越多的证据表明，APP的处理和淀粉样β蛋白(Aβ)的释放是Tau病理的上游，但缺乏模拟人类AD缓慢进展的动物模型提出了围绕这一机制的问题。在这里，我们描述了在成年野生型大鼠中处理类似AD的β应用程序，产生与在AD患者中观察到的类似的人类APP、βCTF和Aβ水平，足以触发渐进性伸张症。Tau的过度磷酸化在老年大鼠形成淀粉样斑块和缠结状聚集体之前几个月就开始了，并且没有相关的炎症。基于超过30个月的纵向特征，我们发现突触外和情绪障碍出现在长时程增强缺陷和记忆衰退之前，因此出现在Aβ和Tau聚集之前。这些令人信服的数据使我们(1)在实验上证实了在体内和不存在Tau转基因过表达的情况下，βAPP处理与Tau病理之间的因果关系，(2)支持淀粉样变致级联反应，(3)提出了前驱AD进展的4步假说。
The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-beta (A beta) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism. Here, we described that an AD-like beta APP processing in adults wild-type rats, yielding to human APP, beta CTF and A beta levels similar to those observed in AD patients, is sufficient to trigger gradual Tauopathy. The Tau hyperphosphorylation begins several months before the formation of both amyloid plaques and tangle-like aggregates in aged rats and without associated inflammation. Based on a longitudinal characterization over 30 months, we showed that extrasynaptic and emotional impairments appear before long-term potentiation deficits and memory decline and so before A beta and Tau aggregations. These compelling data allowed us to (1) experimentally confirm the causal relationship between beta APP processing and Tau pathology in vivo and without Tau transgene overexpression, (2) support the amyloidogenic cascade and (3) propose a 4-step hypothesis of prodromal AD progression.