Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein.
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.
Tamagno
Elena
E
Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy. elena.tamagno@unito.it
Guglielmotto
Michela
M
Aragno
Manuela
M
Borghi
Roberta
R
Autelli
Riccardo
R
Giliberto
Luca
L
Muraca
Giuseppe
G
Danni
Oliviero
O
Zhu
Xiongwei
X
Smith
Mark A
MA
Perry
George
G
Jo
Dong-Gyu
DG
Mattson
Mark P
MP
Tabaton
Massimo
M
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
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