Title: Phosphorylation of the Translation Initiation Factor eIF2 alpha Increases BACE1 Levels and Promotes Amyloidogenesis
Authors: O'Connor, Tracy
Sadleir, Katherine R
Maus, Erika
Velliquette, Rodney A
Zhao, Jie
Cole, Sarah L
Eimer, William A
Hitt, Brian
Bembinster, Leslie A
Lammich, Sven
Lichtenthaler, Stefan F
Hébert, Sébastien
De Strooper, Bart
Haass, Christian
Bennett, David A
Vassar, Robert # ×
Issue Date: 26-Dec-2008
Publisher: Cell Press
Series Title: Neuron vol:60 issue:6 pages:988-1009
Abstract: beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for beta-amyloid (A beta) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2 alpha (eIF2 alpha-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2 alpha-P phosphatase PP1c, directly increases BACE1 and elevates A beta production in primary neurons. Preventing eIF2 alpha phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2 alpha kinase PERK, or PERK inhibitor P58(IPK) blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2 alpha-P, BACE1, A beta, and amyloid plaques. Importantly, eIF2 alpha-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2 alpha-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2 alpha phosphorylation increases BACE1 levels and causes A beta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.
ISSN: 0896-6273
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Molecular Genetics Section (-)
× corresponding author
# (joint) last author

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