Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
School of Medicine and Pharmaceutical Engineering, Taizhou Vocational and Technical College, Taizhou, China.
J Cell Mol Med. 2020 Aug;24(16):9176-9188. doi: 10.1111/jcmm.15555. Epub 2020 Jul 10.
The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.
治疗性低温是治疗与脑外伤相关的脑损伤的有效手段，但它的副作用限制了其在临床常规应用中的使用。低温上调 RNA 结合基序蛋白 3（RBM3），已被证明可以保护突触可塑性。在这里，我们发现 TBI 后一个月的小鼠表现出认知和 LTP 缺陷、棘突丢失、AD 样 tau 病理学。相比之下，在 TBI 小鼠中联合低温预处理（HT），可明显逆转 LTP 和认知缺陷、棘突丢失以及 tau 在几个位点的异常磷酸化。但是，在使用 RBM3 shRNA 阻断 RBM3 表达的情况下，HT 的神经保护作用在 TBI 小鼠模型中消失了。另一方面，通过 AAV-RBM3 质粒过表达 RBM3 可以模拟 HT 样神经保护作用，对抗 TBI 引起的慢性脑损伤，如改善 TBI 小鼠模型中的 LTP 和认知功能、棘突丢失以及 tau 过度磷酸化。综上所述，低温预处理以 RBM3 表达依赖性方式逆转了 TBI 引起的慢性 AD 样病理和行为缺陷，RBM3 可能是包括阿尔茨海默病在内的神经退行性疾病的潜在靶点。
