Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway.
Beta-site APP cleaving enzyme 1 (BACE1) is the rate limiting enzyme for accumulation of amyloid β (Aβ)-peptide in the brain in Alzheimer's disease (AD). Oxidative stress (OS) that leads to metabolic dysfunction and apoptosis of neurons in AD enhances BACE1 expression and activity. The activation of c-jun N-terminal kinase (JNK) pathway was proposed to explain the BACE1 mRNA increase under OS. However, little is known about the translational control of BACE1 in OS. Recently, a post-transcriptional increase of BACE1 level controlled by phosphorylation of eIF2α (eukaryotic translation initiation factor-2α) have been described after energy deprivation. PKR (double-stranded RNA dependant protein kinase) is a pro-apoptotic kinase that phosphorylates eIF2α and modulates JNK activation in various cellular stresses. We investigated the relations between PKR, eIF2α and BACE1 in AD brains in APP/PS1 knock-in mice and in hydrogen peroxide-induced OS in human neuroblastoma (SH-SY5Y) cell cultures. Immunoblotting results showed that activated PKR (pPKR) and activated eIF2α (peIF2α) and BACE1 levels are increased in AD cortices and BACE1 correlate with phosphorylated eIF2α levels. BACE1 protein levels are increased in response to OS in SH-SY5Y cells and specific inhibitions of PKR-eIF2α attenuate BACE1 protein levels in this model. Our findings provide a new translational regulation of BACE1, under the control of PKR in OS, where eIF2α phosphorylation regulates BACE1 protein expression.
Service d'Histologie et de Biologie du Vieillissement, APHP, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, Université Paris VII, Paris, France. francois.mouton-liger@inserm.fr
François
F
Mouton-Liger
Claire
C
Paquet
Julien
J
Dumurgier
Constantin
C
Bouras
Laurent
L
Pradier
Françoise
F
Gray
Jacques
J
Hugon
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015852:Eukaryotic Initiation Factor-2; D006861:Hydrogen Peroxide; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse