Traumatic brain injury (TBI) is one of the important risk factors for the development of Alzheimer’s disease (AD). However, the molecular mechanism by which TBI promotes the progression of AD is not elucidated. In this study, we showed that the abnormal production of E2F1 is a major factor in promoting the neuropathological and cognitive deterioration of AD post-TBI. We found that repeated mild TBI can aggravate the neuropathology of AD in APP/PS1 mice. At the same time, the co-expression of E2F1 and beta-site APP cleaving enzyme 1 (BACE1) was upregulated when the mouse hippocampus was dissected. BACE1 is recognized as a rate-limiting enzyme for the production of Aβ. Here, we speculate that E2F1 may play a role in promoting BACE1 expression in AD. Therefore, we collected peripheral blood from patients with AD. Interestingly, there is a positive correlation between E2F1 and brain-derived neurotrophic factor–antisense (BDNF-AS), whereas BDNF-AS in AD can promote the expression of BACE1 and exhibit a neurotoxic effect. We established a cell model and found a regulatory relationship between E2F1 and BDNF-AS. Therefore, based on our results, we concluded that E2F1 regulates BDNF-AS, promotes the expression of BACE1, and affects the progression of AD. Furthermore, E2F1 mediates the TBI-induced neurotoxicity of AD.

创伤性脑损伤（TBI）是阿尔茨海默病（AD）发展的重要危险因素之一。然而，TBI促进AD进展的分子机制尚未阐明。在这项研究中，我们发现E2F1的异常产生是促进TBI后AD神经病理学和认知功能恶化的主要因素。我们发现反复轻度 TBI 会加重 APP/PS1 小鼠 AD 的神经病理学。同时，当解剖小鼠海马时，E2F1 和 β 位点 APP 裂解酶 1 (BACE1) 的共表达上调。BACE1 被认为是 Aβ 生成的限速酶。在此，我们推测E2F1可能在AD中发挥促进BACE1表达的作用。因此，我们采集了AD患者的外周血。有趣的是，E2F1与脑源性神经营养因子反义（BDNF-AS）之间存在正相关性，而AD中的BDNF-AS可以促进BACE1的表达并表现出神经毒性作用。我们建立了细胞模型，发现了E2F1和BDNF-AS之间的调控关系。因此，根据我们的结果，我们得出结论，E2F1调节BDNF-AS，促进BACE1的表达，并影响AD的进展。此外，E2F1 介导 TBI 诱导的 AD 神经毒性。