Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer’s disease and other tau prion disorders.

野生型和突变型 tau 蛋白都可能错误折叠成朊病毒，并在动物和人的中枢神经系统中自我繁殖。为了扩展其他人的工作，我们研究了表达突变人类 tau (P301S) 的转基因 (Tg) 大鼠中 tau 朊病毒介导的神经变性的分子基础；该Tg大鼠品系被标记为Tg12099。我们使用大鼠Prnp启动子来驱动人类 0N4R 同种型中突变 tau (P301S) 的过度表达。在转基因纯合子 Tg12099(+/+) 大鼠中，突变型人类 tau 蛋白的普遍表达导致磷酸化 tau 蛋白包涵体逐渐积累，包括额叶皮质和边缘系统中的银阳性缠结。在终末Tg12099(+/+)大鼠中发现中枢神经系统功能障碍的迹象，表现出严重的神经变性以及杏仁核和梨状皮层的严重萎缩。 tau 朊病毒活性的最大增加出现在皮质边缘结构中。与纯合子 Tg12099(+/+) 大鼠相比，我们发现半合子大鼠中突变 tau 的水平较低，导致 2 岁以下的神经病理学变化很少。值得注意的是，这些半合子大鼠可以通过脑内接种重组 tau 原纤维或从患病、老年纯合子 Tg12099(+/+) 大鼠的脑匀浆中沉淀的 tau 朊病毒来感染。我们的研究认为，Tg12099 大鼠中 tau 朊病毒的区域传播和神经变性与人类原发性 tau 蛋白病中发现的情况相似。这些发现似乎可能会增进我们对人类 tau 蛋白病的理解，并可能为阿尔茨海默病和其他 tau 蛋白疾病提供有效的治疗方法。