Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA, 94158, USA.
Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, 94158, USA.
Acta Neuropathol. 2024 Aug 20;148(1):25. doi: 10.1007/s00401-024-02771-5.
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 蛋白都可以错误折叠成朊病毒，并在动物和人类的中枢神经系统中自我传播。为了扩展其他人的工作，我们研究了在表达突变型人 tau（P301S）的转基因（Tg）大鼠中 tau 朊病毒介导的神经退行性变的分子基础；这条 Tg 大鼠线被标记为 Tg12099。我们使用大鼠 Prnp 启动子驱动突变型 tau（P301S）在人 0N4R 同工型中的过表达。在 Tg12099(+/+)大鼠中，转基因的纯合子中，突变型人 tau 的普遍表达导致磷酸化 tau 包含物的进行性积累，包括额皮质和边缘系统中的银阳性缠结。在表现出严重神经退行性变和杏仁核和梨状皮质明显萎缩的终末 Tg12099(+/+)大鼠中发现了中枢神经系统功能障碍的迹象。在皮质边缘结构中发现 tau 朊病毒活性的最大增加。与纯合子 Tg12099(+/+)大鼠相比，我们在杂合子大鼠中发现突变型 tau 的水平较低，导致高达 2 岁时很少有神经病理学变化。值得注意的是，这些杂合子大鼠可以通过脑内接种重组 tau 纤维或从患病、年老的纯合子 Tg12099(+/+)大鼠脑匀浆中沉淀的 tau 朊病毒感染。我们的研究表明，Tg12099 大鼠中 tau 朊病毒的区域性传播和神经退行性变类似于人类原发性 tau 病中发现的情况。这些发现似乎有可能促进我们对人类 tau 病的理解，并可能导致针对阿尔茨海默病和其他 tau 朊病毒疾病的有效治疗方法。
