Park Hyo-Jin, Ran Yong, Jung Joo In, Holmes Oliver, Price Ashleigh R, Smithson Lisa, Ceballos-Diaz Carolina, Han Chul, Wolfe Michael S, Daaka Yehia, Ryabinin Andrey E, Kim Seong-Hun, Hauger Richard L, Golde Todd E, Felsenstein Kevin M
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA Department of Pharmacology and Therapeutics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
EMBO J. 2015 Jun 12;34(12):1674-86. doi: 10.15252/embj.201488795. Epub 2015 May 11.
The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase.
压力与阿尔茨海默病（AD）风险之间的生物学关联尚不清楚。我们研究了促肾上腺皮质激素释放因子（CRF），一种关键的应激反应介质，如何影响β-淀粉样蛋白（Aβ）的产生。在细胞中，CRF处理会增加Aβ的产生，并触发CRF受体1（CRFR1）和γ-分泌酶内化。免疫共沉淀研究表明γ-分泌酶与CRFR1相关联；这是由β-抑制蛋白结合基序介导的。此外，CRFR1和γ-分泌酶在脂筏组分中共定位，CRF处理后γ-分泌酶积累增加。CRF处理还会增加体外γ-分泌酶活性，揭示了第二种不依赖受体的作用机制。CRF是第一种被证明可直接调节γ-分泌酶活性的内源性神经肽。出乎意料的是，CRFR1拮抗剂也会增加Aβ。这些数据共同将CRF与通过γ-分泌酶增加的Aβ联系起来，并为压力如何增加AD风险提供了机制性见解。它们还表明，直接靶向CRF可能是有效调节该途径以获得AD治疗益处所必需的，因为CRFR1拮抗剂会增加Aβ，并且在某些情况下通过对γ-分泌酶的复杂作用优先增加Aβ42。
