Mohamed Ahmed Sabry, ElKaffas Mahmoud, Metwally Karim, Abdelfattah Mahmoud, Elsery Eslam Ashraf, Elshazly Ahmed, Gomaa Hossam Eldin, Alsayed Aziza, El-Desouky Sara, El-Gamal Randa, Elfarrash Sara
Program of Medicine, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
Mansoura Manchester Medical Program, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
J Inflamm (Lond). 2024 Aug 6;21(1):29. doi: 10.1186/s12950-024-00396-9.
Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant hyperphoshorylated tau filaments, the associated neuroinflammation and disease phenotype. However, the exact underpinning mechanisms are still not fully addressed that hinder our understanding of the tauopathy diseases and the development of possible therapeutic targets.Methods: In the current study, hippocampus from three disease time points (2, 4 and 6 months) of P301S mice were further characterized in comparison to the age and sex matched control wild type mice (WT) that do not express the transgene. Different spectrum of hippocampal dependent cognitive tests, biochemical and pathological analysis were conducted to understand the disease progression and the associated changes in each stage. Results: Cognitive impairment was manifested as early as 2 months age, prior to the identification of tau aggregation and phosphorylation by immunostaining. P301S mice manifested an increased pro-inflammatory related changes at mRNA transcription level (IL-1b and IL17A) with the progression of the disease and when compared to the WT mice of the same age. Among the identified genes in the current study, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) genes expression that is considered as the master regulator of an endogenous inducible defense system was significantly impaired in P301S mice by 4 and 6 months when compared to healthy WT controls. A data that was also supported by the immunostaining of the serial brain sections including the both brain stem and hippocampus. The current result is suggesting that the downregulation of Nrf2 gene and the impaired Nrf2 dependent anti-inflammatory mechanisms in P301S mice brain is possibly contributing -among other factors- in the neuroinflammation and tauopathy, and that modulation of Nrf2 signaling impairments can be further investigated as a promising potential therapeutic target for tauopathy.
转人类P301S tau蛋白基因的小鼠表现出许多人类tau蛋白病的特征，包括形成大量高度磷酸化的tau细丝、相关的神经炎症和疾病表型。然而，确切的潜在机制仍未完全阐明，这阻碍了我们对tau蛋白病的理解以及可能的治疗靶点的开发。方法：在本研究中，与不表达转基因的年龄和性别匹配的对照野生型小鼠（WT）相比，对P301S小鼠三个疾病时间点（2、4和6个月）的海马进行了进一步表征。进行了不同范围的海马依赖性认知测试、生化和病理分析，以了解疾病进展以及每个阶段的相关变化。结果：早在2个月龄时就出现了认知障碍，早于通过免疫染色鉴定tau聚集和磷酸化之前。随着疾病的进展，与同年龄的WT小鼠相比，P301S小鼠在mRNA转录水平（IL-1β和IL17A）表现出促炎相关变化增加。在本研究中鉴定的基因中，与健康的WT对照相比，在4个月和6个月时，被认为是内源性诱导防御系统主要调节因子的核因子（红细胞衍生样2）-样2（Nrf2）基因表达在P301S小鼠中显著受损。包括脑干和海马在内的连续脑切片的免疫染色也支持了这一数据。目前的结果表明，P301S小鼠脑中Nrf2基因的下调和Nrf2依赖性抗炎机制的受损可能在神经炎症和tau蛋白病中起作用（在其他因素中），并且Nrf2信号损伤的调节可作为tau蛋白病有前景的潜在治疗靶点进一步研究。
