Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP x tau transgenic mice
Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP x tau transgenic mice
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DOI：
10.2353/ajpath.2007.070403
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发表时间：
2007-12-01
影响因子：
6
通讯作者：
Jucker, Mathias
中科院分区：
文献类型：
--
作者：
Bolmont, Tristan;Clavaguera, Florence;Jucker, Mathias
阿尔茨海默病在形态学上表现为老年斑，主要由细胞外β -淀粉样蛋白（Aβ）沉积形成，以及神经原纤维病变，后者由过度磷酸化的tau蛋白在细胞内聚集而成。为了研究tau病理在体内的诱导情况，将来自年老的有Aβ沉积的APP23转基因小鼠的脑提取物脑内注射到年轻的B6/P301L tau转基因小鼠体内。注射6个月后，在注射的海马体中诱导出了tau病理，而且在远离注射部位的脑区，如内嗅皮层和杏仁核（这些区域的神经元投射到注射部位）也诱导出了tau病理。当注射来自年老的非转基因对照小鼠和年老的有tau沉积的B6/P301L转基因小鼠的脑提取物时，未观察到或仅观察到轻微的tau诱导现象。为了进一步研究Aβ诱导的tau病变，将B6/P301L tau转基因小鼠与APP23小鼠杂交。尽管双转基因小鼠中的Aβ沉积与单APP23转基因小鼠没有差异，但与单B6/P301L tau转基因小鼠相比，双转基因小鼠显示出tau病理增加，主要在Aβ斑块负荷高的区域。目前的研究结果表明，提取物来源的Aβ种类和沉积的纤维状Aβ都能诱导tau神经原纤维病理的形成。注射的Aβ在没有Aβ沉积的情况下能触发tau病理这一观察结果，为阿尔茨海默病大脑中Aβ沉积的神经解剖位置与tau病变的发展和扩散之间的差异提供了一种解释。
Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyper-phosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A beta-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta. deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.