Constitutive JAK2/STAT1 activation regulates endogenous BACE1 expression in neurons.
The protease BACE1 (beta-site APP-cleaving enzyme 1) is essential for the generation of amyloid beta (Abeta) from amyloid precursor protein (APP). Although BACE1 is expressed primarily in neurons, which are a principal source of Abeta in the brain, the mechanism that underlies basal expression of BACE1 in neurons has not been studied thoroughly. In the present study, we found that endogenous BACE1 expression was mediated by constitutive JAK2/STAT1 activation in neurons. Inhibition of the JAK2/STAT1 signaling pathway, using AG490 (a JAK2 inhibitor), a dominant-negative form of STAT1, and SOCS1 and SOCS3 overexpression, reduced levels of BACE1 promoter activity, expression of endogenous BACE1, and generation of Abeta. These results were recapitulated in the SH-SY5Y neuronal cell line, primary cultured neurons, and mouse brains. Therefore, we propose that constitutive JAK2/STAT1 activation mediates endogenous BACE1 expression in neurons and that inhibition of JAK2/STAT1 signaling abrogates basal levels of BACE1 expression and Abeta generation.
Cho
Hyun Jin
HJ
Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Jongrogu, Seoul, Republic of Korea.
Jin
Seok Min
SM
Son
Sung Min
SM
Kim
Yong Woo
YW
Hwang
Ji Yeon
JY
Hong
Hyun Seok
HS
Mook-Jung
Inhee
I
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D053614:Janus Kinase 2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human