Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways.
4-Hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, up-regulates expression of the beta-site APP cleaving enzyme (BACE-1), an aspartyl protease responsible for the beta-secretase cleavage of amyloid precursor protein (AbetaPP), and results in increased levels of amyloid beta (Abeta) peptide. The mechanisms underlying this remain unclear but are of fundamental importance because prevention of BACE-1 up-regulation is viewed as an important therapeutic strategy. In this study, we exposed NT(2) neurons to a range of HNE concentrations (0.5-5 microm) that elicited an up-regulation of BACE-1 expression, a significant increase in intracellular and secreted levels of Abeta peptides as well as apoptosis involving poly-ADP ribose polymerase cleavage and activation of caspase 3. To delineate the molecular events involved in HNE-mediated BACE-1 activation, we investigated the involvement of stress-activated protein kinases (SAPK), signal transducers and activators of transcription (STAT) and serine-threonine kinase B/phosphatidylinositol phosphate 3 kinase (Akt/PtdIns3K). Using specific pharmacological inhibitors, our results show that activation of c-Jun N-terminal kinases and p38(MAPK.), but not STAT or Akt/PtdIns3K, pathways mediate the HNE-dependent up-regulation of BACE-1 expression. Therefore, HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer's disease by selectively activating SAPK pathways and BACE-1 that regulate the proteolytic processing of AbetaPP.
Tamagno
Elena
E
Department of Experimental Medicine and Oncology, General Pathology Section, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. Elena.Tamagno@unito.it
Parola
Maurizio
M
Bardini
Paola
P
Piccini
Alessandra
A
Borghi
Roberta
R
Guglielmotto
Michela
M
Santoro
Gianni
G
Davit
Annalisa
A
Danni
Oliviero
O
Smith
M A
MA
Perry
G
G
Tabaton
Massimo
M
D000447:Aldehydes / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D017209:Apoptosis / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000447:Aldehydes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D020536:Enzyme Activators; D048031:JNK Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; C494079:STAT1 protein, human; C494918:AKT1 protein, human; C509280:BACE1 protein, human; C027576:4-hydroxy-2-nonenal