Microangiopathy, including proliferation of small diameter capillaries, increasing vessel tortuosity, and increased capillary blockage by leukocytes, was previously observed in the aged rTg4510 mouse model. Similar gene expression changes related to angiogenesis were observed in both rTg4510 and Alzheimer’s disease (AD). It is uncertain if tau is directly responsible for these vascular changes by interacting directly with microvessels, and/or if it contributes indirectly via neurodegeneration and concurrent neuronal loss and inflammation. To better understand the nature of tau-related microangiopathy in human AD and in tau mice, we isolated capillaries and observed that bioactive soluble tau protein could be readily detected in association with vasculature. To examine whether this soluble tau is directly responsible for the microangiopathic changes, we made use of the tetracycline-repressible gene expression cassette in the rTg4510 mouse model and measured vascular pathology following tau reduction. These data suggest that reduction of tau is insufficient to alter established microvascular complications including morphological alterations, enhanced expression of inflammatory genes involved in leukocyte adherence, and blood brain barrier compromise. These data imply that 1) soluble bioactive tau surprisingly accumulates at the blood brain barrier in human brain and in mouse models, and 2) the morphological and molecular phenotype of microvascular disturbance does not resolve with reduction of whole brain soluble tau. Additional consideration of vascular-directed therapies and strategies that target tau in the vascular space may be required to restore normal function in neurodegenerative disease.

中文翻译：

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老年小鼠 Tau 蛋白的减少不会影响微血管病。

先前在老年 rTg4510 小鼠模型中观察到微血管病变，包括小直径毛细血管增殖、血管迂曲度增加和白细胞阻塞毛细血管增加。在 rTg4510 和阿尔茨海默病 (AD) 中观察到与血管生成相关的类似基因表达变化。目前尚不清楚 tau 蛋白是否通过与微血管直接相互作用而直接导致这些血管变化，和/或是否通过神经退行性变以及并发的神经元丢失和炎症间接起作用。为了更好地了解人类 AD 和 tau 小鼠中 tau 相关微血管病的性质，我们分离了毛细血管，并观察到可以很容易地检测到与脉管系统相关的生物活性可溶性 tau 蛋白。为了检查这种可溶性 tau 是否直接导致微血管病变变化，我们在 rTg4510 小鼠模型中使用了四环素抑制基因表达盒，并测量了 tau 减少后的血管病理学。这些数据表明，tau 蛋白的减少不足以改变已确定的微血管并发症，包括形态改变、参与白细胞粘附的炎症基因表达增强以及血脑屏障受损。这些数据表明：1）可溶性生物活性 tau 蛋白令人惊讶地在人脑和小鼠模型的血脑屏障处积聚，2）微血管紊乱的形态和分子表型不会随着全脑可溶性 tau 蛋白的减少而得到解决。为了恢复神经退行性疾病的正常功能，可能需要额外考虑针对血管空间中的 tau 蛋白的血管定向治疗和策略。