TY - JOUR
T1 - Phosphorylation of the Translation Initiation Factor eIF2α Increases BACE1 Levels and Promotes Amyloidogenesis
AU - O'Connor, Tracy
AU - Sadleir, Katherine R.
AU - Maus, Erika
AU - Velliquette, Rodney A.
AU - Zhao, Jie
AU - Cole, Sarah L.
AU - Eimer, William A.
AU - Hitt, Brian
AU - Bembinster, Leslie A.
AU - Lammich, Sven
AU - Lichtenthaler, Stefan F.
AU - Hébert, Sébastien S.
AU - De Strooper, Bart
AU - Haass, Christian
AU - Bennett, David A.
AU - Vassar, Robert
N1 - Funding Information:
We thank Richard Scarpulla for key intellectual contributions to this work and general expertise in the area of energy metabolism, Adriana Ferreira for expertise in neuronal cultures, and Marina Yasvoina and Peizhen Shao for performing tissue sectioning and immunohistochemistry. Human AD brain tissue samples were a gift from participants in Rush Hospital Memory and Aging Project (R01AG17917; Bennett, David A.; PI). GADD34ΔN, GADD34 transfection control, PERKDN, and P58 IPK constructs were generous gifts from David Ron (New York University) and the GCN2DN construct was a gift from Dr. Ron Wek (University of Indiana). The PS1-NT antibody was a gift of Gopal Thinakaran (University of Chicago). This work was supported by the John Douglas French Foundation (S.L.C.), and NIH grants 5T32AG020506-04 (T.O.), 1F31AG030965-01A1 (T.O.), 5T32AG000260 (K.R.S. and R.A.V.), R01 AG022560 (R.V.), and R01 AG030142 (R.V.). C.H., S.F.L., and S.L. are supported by grants from the Deutsche Forschungsgemeinschaft (SFB 596) and the Federal Ministry of Education and Research (NGFN-Alzheimer Disease - Ig), and B.D.S. and S.H. by a Methusalem grant from the Flemisch Government.
PY - 2008/12/26
Y1 - 2008/12/26
N2 - 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.
AB - 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.
KW - CELLBIO
KW - HUMDISEASE
KW - MOLNEURO
UR - https://www.scopus.com/pages/publications/57649245230
U2 - 10.1016/j.neuron.2008.10.047
DO - 10.1016/j.neuron.2008.10.047
M3 - Article
C2 - 19109907
AN - SCOPUS:57649245230
SN - 0896-6273
VL - 60
SP - 988
EP - 1009
JO - Neuron
JF - Neuron
IS - 6
ER -
SDG 3 Good Health and Well-being