Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
Mol Neurobiol. 2021 Oct;58(10):5224-5238. doi: 10.1007/s12035-021-02471-1. Epub 2021 Jul 17.
Accumulated beta-amyloid (Aβ) in the brain is the hallmark of Alzheimer's disease (AD). Despite Aβ accumulation is known to trigger cellular dysfunctions and learning and memory damage, the detailed molecular mechanism remains elusive. Recent studies have shown that the onset of memory impairment and learning damage in the AD animal is different, suggesting that the underlying mechanism of the development of memory impairment and learning damage may not be the same. In the current study, with the use of Aβ42 transgenic flies as models, we found that Aβ induces memory damage and learning impairment via differential molecular signaling pathways. In early stage, Aβ activates both Ras and PI3K to regulate Rac1 activity, which affects mostly on memory performance. In later stage, PI3K-Akt is strongly activated by Aβ, which leads to learning damage. Moreover, reduced Akt, but not Rac1, activity promotes cell viability in the Aβ42 transgenic flies, indicating that Akt and Rac1 exhibit differential roles in Aβ regulating toxicity. Taken together, different molecular and cellular mechanisms are involved in Aβ-induced learning damage and memory decline; thus, caution should be taken during the development of therapeutic intervention in the future.
脑内β-淀粉样蛋白（Aβ）的积累是阿尔茨海默病（AD）的标志。尽管众所周知，Aβ的积累会引发细胞功能障碍和学习记忆损伤，但详细的分子机制仍难以捉摸。最近的研究表明，AD 动物的记忆损伤和学习损伤的发病机制不同，这表明记忆损伤和学习损伤的发展的潜在机制可能并不相同。在本研究中，我们使用 Aβ42 转基因果蝇作为模型，发现 Aβ 通过不同的分子信号通路诱导记忆损伤和学习损伤。在早期，Aβ 激活 Ras 和 PI3K 以调节 Rac1 活性，这主要影响记忆表现。在后期，Aβ 强烈激活 PI3K-Akt，导致学习损伤。此外，Aβ42 转基因果蝇中 Akt 的活性降低，但 Rac1 的活性没有降低，这表明 Akt 和 Rac1 在 Aβ 调节毒性方面发挥了不同的作用。总之，不同的分子和细胞机制参与了 Aβ 诱导的学习损伤和记忆下降；因此，在未来的治疗干预措施的开发中应谨慎行事。
