Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China.
Department of Clinical Laboratory, Beijing Huairou Hospital, Beijing, People's Republic of China.
Aging Cell. 2024 Oct;23(10):e14260. doi: 10.1111/acel.14260. Epub 2024 Jul 12.
Amyloid plaques, a major pathological hallmark of Alzheimer's disease (AD), are caused by an imbalance between the amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein (APP). BACE1 cleavage of APP is the rate-limiting step for amyloid-β production and plaque formation in AD. Although the alteration of BACE1 expression in AD has been investigated, the underlying mechanisms remain unknown. In this study, we determined MEIS2 was notably elevated in AD models and AD patients. Alterations in the expression of MEIS2 can modulate the levels of BACE1. MEIS2 downregulation improved the learning and memory retention of AD mice and decreased the number of amyloid plaques. MEIS2 binds to the BACE1 promoter, positively regulates BACE1 expression, and accelerates APP amyloid degradation in vitro. Therefore, our findings suggest that MEIS2 might be a critical transcription factor in AD, since it regulates BACE1 expression and accelerates BACE1-mediated APP amyloidogenic cleavage. MEIS2 is a promising early intervention target for AD treatment.
淀粉样斑块是阿尔茨海默病（AD）的主要病理学标志，是由淀粉样前体蛋白（APP）的淀粉样生成和非淀粉样生成途径之间的失衡引起的。BACE1 对 APP 的切割是 AD 中β-淀粉样蛋白产生和斑块形成的限速步骤。尽管已经研究了 AD 中 BACE1 表达的改变，但潜在机制仍不清楚。在这项研究中，我们确定 MEIS2 在 AD 模型和 AD 患者中明显升高。MEIS2 的表达改变可以调节 BACE1 的水平。MEIS2 的下调改善了 AD 小鼠的学习和记忆保留，并减少了淀粉样斑块的数量。MEIS2 结合到 BACE1 启动子上，正向调节 BACE1 的表达，并在体外加速 APP 淀粉样降解。因此，我们的研究结果表明，MEIS2 可能是 AD 中的一个关键转录因子，因为它调节 BACE1 的表达并加速 BACE1 介导的 APP 淀粉样生成切割。MEIS2 是 AD 治疗的一个有前途的早期干预靶点。
