Tang Siqi, Luo Wenshu, Cheng Cheng, Shen Leshan, Wu Xia, Xiao Xiao
School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Belief Biomed Inc, Shanghai, 200237, China.
Biochem Biophys Rep. 2025 Jun 17;43:102089. doi: 10.1016/j.bbrep.2025.102089. eCollection 2025 Sep.
Brain-derived neurotrophic factor (BDNF) protects neurons from degeneration, making it a promising therapeutic target for Alzheimer's disease (AD). However, the genetic regulation resulting from BDNF overexpression in the brain remains to be further illustrated. Using APP/PS1 and rTg4510 mouse models, we analyzed hippocampal transcriptomes after intrahippocampal AAVT42- injection. In APP/PS1 mice with Aβ accumulation, BDNF upregulated genes involved in neuronal signaling and downregulated neurodegenerative pathways. In rTg4510 mice with p-tau pathology, upregulated genes were associated with cell differentiation and neuronal development, while downregulated genes were related to metabolism and biosynthesis. A comparison of differentially expressed genes (DEGs) between the two strains identified eight commonly upregulated genes () and two downregulated genes (, ). Notably, three genes - , -were upregulated in both models, suggesting shared neuroprotective mechanisms. These findings reveal distinct and common genetic responses to BDNF in Aβ and p-tau pathogenesis, supporting its potential as a therapeutic strategy for AD.
脑源性神经营养因子（BDNF）可保护神经元免于退化，使其成为治疗阿尔茨海默病（AD）的一个有前景的治疗靶点。然而，BDNF在大脑中过表达所导致的基因调控仍有待进一步阐明。利用APP/PS1和rTg4510小鼠模型，我们分析了海马内注射腺相关病毒载体（AAVT42-）后的海马转录组。在有Aβ积累的APP/PS1小鼠中，BDNF上调了参与神经元信号传导的基因，并下调了神经退行性通路。在有p- tau病理变化的rTg4510小鼠中，上调的基因与细胞分化和神经元发育相关，而下调的基因与代谢和生物合成有关。对这两个品系之间的差异表达基因（DEGs）进行比较，确定了八个共同上调的基因（ ）和两个下调的基因（ ， ）。值得注意的是，三个基因—— 、 在两个模型中均上调，表明存在共同的神经保护机制。这些发现揭示了在Aβ和p- tau发病机制中对BDNF的不同和共同的基因反应，支持了其作为AD治疗策略的潜力。
