Ferritin light chain interacts with PEN-2 and affects ¦Ã-secretase activity

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• 作者：Xinxin Li ; Yiqian Liu ; Qiuyang Zheng ; Guorui Yao ; Peng Cheng ; Guojun Bu ; Huaxi Xu ; Yun-wu Zhang
• 关键词：A¦Â ; ¦Â-amyloid ; AD ; Alzheimer's disease ; APP ; ¦Â-amyloid precursor protein ; CTF ; carboxyl-terminal fragment ; FTH ; ferritin heavy chain ; FTL ; ferritin light chain ; HEK293Swe ; HEK293 cells stably expressing human APP Swedish mutations ; NICD ; notch intracel
• 刊名：Neuroscience Letters
• 出版年：2013
• 出版时间：26 August, 2013
• 年：2013
• 卷：548
• 期：Complete
• 页码：90-94
• 全文大小：1002 K

文摘

Alzheimer's disease (AD) is primarily caused by overproduction/deposition of ¦Â-amyloid (A¦Â) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects ¦Â-amyloid precursor protein (APP) expression and A¦Â deposition, detailed role of iron in AD requires further elucidation. A¦Â is produced by sequential proteolytic cleavages of APP by ¦Â-secretase and ¦Ã-secretase. The ¦Ã-secretase complex comprises presenilins (PS1 or PS2), nicastrin, APH-1, and PEN-2. Herein, we find that PEN-2 can interact with ferritin light chain (FTL), an important component of the iron storage protein ferritin. In addition, we show that overexpression of FTL increases the protein levels of PEN-2 and PS1 amino-terminal fragment (NTF) and promotes ¦Ã-secretase activity for more production of A¦Â and notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PS1 NTF and promote ¦Ã-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PS1 NTF. Together, our results suggest that iron can increase ¦Ã-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/¦Ã-secretase and A¦Â generation in AD.