Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis

Neuron 60(6): 988-1009

Authors/Editors: O'Connor T
Sadleir KR
Maus E
Velliquette RA
Zhao J
Cole SL
Eimer WA
Hitt B
Bembinster LA
Lammich S
Hebert SS
De Strooper B
Haass C
Bennett DA
Vassar R
Publication Date: 2008
Type of Publication: Journal Article
beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for beta-amyloid (Abeta) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2alpha (eIF2alpha-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2alpha-P phosphatase PP1c, directly increases BACE1 and elevates Abeta production in primary neurons. Preventing eIF2alpha phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2alpha 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 eIF2alpha-P, BACE1, Abeta, and amyloid plaques. Importantly, eIF2alpha-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2alpha-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.

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