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

Alzheimer's disease (AD) is primarily caused by overproduction/deposition of beta-amyloid (A beta) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects beta-amyloid precursor protein (APP) expression and A beta deposition, detailed role of iron in AD requires further elucidation. A beta is produced by sequential proteolytic cleavages of APP by beta-secretase and gamma-secretase. The gamma-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 PSI amino-terminal fragment (NTF) and promotes gamma-secretase activity for more production of A beta and notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PSI NTF and promote gamma-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PSI NTF. Together, our results suggest that iron can increase gamma-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/gamma-secretase and A beta generation in AD. (C) 2013 Elsevier Ireland Ltd. All rights reserved.