APP家族是内溶酶体膜脆弱性的调节者
Brianna Lundin1, Natalia Wieckiewicz1, Midori Yokomizo1
1MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
The Journal of biological chemistry
|September 29, 2025
概括
粉样蛋白前体蛋白 (APP) 和APLP2可以保护内溶酶体膜免受泄漏. 这些蛋白质的损失增加了脆弱性,这表明它在膜完整性和细胞防御方面发挥了新的作用.
科学领域:
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
- 生物化学 生化学
背景情况:
- 阿尔茨海默病涉及粉样蛋白-β (Aβ) 的积累,由粉样蛋白前体蛋白 (APP) 裂变产生的.
- APP及其家族成员,如粉样前体类蛋白2 (APLP2) 的生理作用尚未完全理解.
- 通过γ-分泌酶进行的APP C99处理发生在内溶酶体内.
研究的目的:
- 调查APP和APLP2在维护内溶酶体膜完整性方面的作用.
- 探索APP/APLP2缺乏对细胞易受各种压力因素的影响.
- 阐明APP在膜稳定性中的功能背后的分子机制.
主要方法:
- 利用CRISPR/Cas9产生APP/APLP2双淘汰 (dKO) 鼠胚胎纤维细胞 (MEF) 细胞.
- 通过氧化应激,腺相关病毒 (AAV) 和陶化试验评估了内溶体膜脆弱性.
- 使用质谱学分析了MEF细胞膜的脂质概况.
- 在初级小脑和皮层神经元中比较APP表达水平和膜脆弱性.
主要成果:
- 与野生型 (WT) 对照组相比,APP/APLP2 dKO MEF 细胞表现出增加的内溶体膜泄漏.
- 过度表达APP部分挽救了dKO细胞中增加的膜脆弱性.
- 在dKO细胞膜中观察到明显的脂质特征,包括胆固醇和Hex1Cer的升高.
- 与皮层神经元相比,具有较高APP表达的小脑神经元显示出较低的内溶体膜脆弱性.
结论:
- APP和APLP2在调节内溶酶体膜脆弱性方面发挥着至关重要的作用.
- 这些蛋白质有助于细胞防御各种压力因素引起的膜损伤.
- 脂质组成的变化可能是APP/APLP2在膜稳定性方面的保护作用的基础.
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