Phosphorylation of the Translation Initiation Factor eIF2α Increases BACE1 Levels and Promotes Amyloidogenesis

Tracy O'Connor, Katherine R. Sadleir, Erika Maus, Rodney A. Velliquette, Jie Zhao, Sarah L. Cole, William A. Eimer, Brian Hitt, Leslie A. Bembinster, Sven Lammich, Stefan F. Lichtenthaler, Sébastien S. Hébert, Bart De Strooper, Christian Haass, David A. Bennett, Robert Vassar*

*Corresponding author for this work

Research output: Contribution to journalArticle

293 Scopus citations

Abstract

β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for β-amyloid (Aβ) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2α (eIF2α-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2α-P phosphatase PP1c, directly increases BACE1 and elevates Aβ production in primary neurons. Preventing eIF2α phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2α kinase PERK, or PERK inhibitor P58IPK blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2α-P, BACE1, Aβ, and amyloid plaques. Importantly, eIF2α-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2α-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2α phosphorylation increases BACE1 levels and causes Aβ overproduction, which could be an early, initiating molecular mechanism in sporadic AD.

Original languageEnglish (US)
Pages (from-to)988-1009
Number of pages22
JournalNeuron
Volume60
Issue number6
DOIs
StatePublished - Dec 26 2008

Keywords

  • CELLBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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    O'Connor, T., Sadleir, K. R., Maus, E., Velliquette, R. A., Zhao, J., Cole, S. L., Eimer, W. A., Hitt, B., Bembinster, L. A., Lammich, S., Lichtenthaler, S. F., Hébert, S. S., De Strooper, B., Haass, C., Bennett, D. A., & Vassar, R. (2008). Phosphorylation of the Translation Initiation Factor eIF2α Increases BACE1 Levels and Promotes Amyloidogenesis. Neuron, 60(6), 988-1009. https://doi.org/10.1016/j.neuron.2008.10.047