Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis.
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.
O'Connor
Tracy
T
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sadleir
Katherine R
KR
Maus
Erika
E
Velliquette
Rodney A
RA
Zhao
Jie
J
Cole
Sarah L
SL
Eimer
William A
WA
Hitt
Brian
B
Bembinster
Leslie A
LA
Lammich
Sven
S
Lichtenthaler
Stefan F
SF
Hébert
Sébastien S
SS
De Strooper
Bart
B
Haass
Christian
C
Bennett
David A
DA
Vassar
Robert
R
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
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