title: Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein.
abstract: Sequential cleavages of the beta-amyloid precursor protein cleaving enzyme 1 (BACE1) by beta-secretase and gamma-secretase generate the amyloid beta-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. Here we show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein. Moreover, BACE1 is induced in association with OS in the brains of mice subjected to cerebral ischaemia/reperfusion. The OS-induced BACE1 expression correlates with an activation of JNK and c-jun, but is absent in cultured cells or mice lacking JNK. Our findings suggest a mechanism by which OS induces BACE1 transcription, thereby promoting production of pathological levels of amyloid beta in AD.
authors.affiliation: Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy. elena.tamagno@unito.it
authors.forename: Elena
authors.initials: E
authors.lastname: Tamagno
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.forename: Roberta
authors.initials: R
authors.lastname: Borghi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Autelli
authors.forename: Luca
authors.initials: L
authors.lastname: Giliberto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Muraca
authors.forename: Oliviero
authors.initials: O
authors.lastname: Danni
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D048670:MAP Kinase Kinase 4 / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D053763:Presenilins / Q000172:deficiency; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053763:Presenilins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse