title: Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: O'Connor
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Sadleir
authors.forename: Erika
authors.initials: E
authors.lastname: Maus
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Velliquette
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Cole
authors.forename: William A
authors.initials: WA
authors.lastname: Eimer
authors.forename: Brian
authors.initials: B
authors.lastname: Hitt
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bembinster
authors.forename: Sven
authors.initials: S
authors.lastname: Lammich
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003292:Convulsants / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000963:Antimetabolites; D016282:Aspartic Acid Endopeptidases; D003292:Convulsants; D003609:Dactinomycin; D003847:Deoxyglucose; D005947:Glucose; D009574:Nitro Compounds; D010446:Peptide Fragments; D011422:Propionates; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D019892:eIF-2 Kinase; C078592:amyloid beta-protein (1-40); C101003:ELF2 protein, human; C509280:BACE1 protein, human; C015392:3-nitropropionic acid