Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer’s disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.

过度磷酸化 tau 蛋白的异常积累会诱发神经退行性疾病（如阿尔茨海默病）的发病机制。已知具有肽基-脯氨酰顺/反异构酶 (PPIase) 活性的分子伴侣可调节这些过程。此前，体外研究表明，52 kDa FK506 结合蛋白 (FKBP52) 与 tau 相互作用，诱导其寡聚化和原纤维形成，从而促进毒性。因此，我们假设 tau 转基因小鼠大脑中 FKBP52 表达的增加会改变 tau 磷酸化和神经原纤维缠结形成，最终导致记忆障碍。为了对此进行测试，tau 转基因 (rTg4510) 和野生型小鼠接受双侧海马注射病毒过表达 FKBP52 或 GFP 对照。我们检查了海马体依赖性记忆、突触可塑性、tau 磷酸化状态和神经元健康。这项工作表明，过表达 FKBP52 的 rTg4510 小鼠空间学习受损，并伴有长期增强缺陷和海马神经元丢失，这与总半胱天冬酶 12 的适度增加有关。与之前的研究一起，我们的研究结果表明 FKBP52 可能使神经元敏感通过激活半胱天冬酶依赖性途径导致 tau 介导的功能障碍，从而导致记忆和学习障碍。