The cytoplasmic domain of Alzheimer's amyloid-beta protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinase-mediated neurotoxic signal via dimerization.
The biological function of full-length amyloid-beta protein precursor (AbetaPP), the precursor of Abeta, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface AbetaPP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of AbetaPP (AbetaPPCD) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with AbetaPPCD (EGFR/AbetaPP hybrids), EGF drastically enhanced neuronal cell death in a manner sensitive to acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-aldehyde (Ac-DEVD-CHO; DEVD), GSH-ethyl ester (GEE), and pertussis toxin (PTX). Dominant-negative apoptosis signal-regulating kinase 1 (ASK1) blocked this neuronal cell death, but not alpha-synuclein-induced cell death. Constitutively active ASK1 (caASK1) caused DEVD/GEE-sensitive cell death in a manner resistant to PTX and sensitive to Humanin, which also suppressed neuronal cell death by EGFR/AbetaPP hybrid. ASK1 formed a complex with AbetaPPCD via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/AbetaPP hybrid-induced and caASK1-induced neuronal cell deaths were specifically blocked by SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one), a specific JNK inhibitor. Combined with our earlier study, these data indicate that dimerization of AbetaPPCD triggers ASK1/JNK-mediated neuronal cell death. We also noticed a potential role of ASK1/JNK in sustaining the activity of this mechanism after initial activation by AbetaPP, which allows for the achievement of cell death by short-term anti-AbetaPP antibody treatment. Understanding the function of AbetaPPCD and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.
Hashimoto
Yuichi
Y
Department of Pharmacology, KEIO University School of Medicine, Medical Research Center, Tokyo, Japan.
Niikura
Takako
T
Chiba
Tomohiro
T
Tsukamoto
Emi
E
Kadowaki
Hisae
H
Nishitoh
Hideki
H
Yamagishi
Yohichi
Y
Ishizaka
Miho
M
Yamada
Marina
M
Nawa
Mikiro
M
Terashita
Kenzo
K
Aiso
Sadakazu
S
Ichijo
Hidenori
H
Nishimoto
Ikuo
I
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006822:Hybrid Cells; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D002352:Carrier Proteins; D005419:Flavonoids; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; C490666:MAPK8IP1 protein, human; C490665:Mapk8ip protein, mouse; C110528:Mapk8ip1 protein, rat; D009842:Oligopeptides; D011506:Proteins; D011725:Pyridines; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C427211:humanin; C432165:pyrazolanthrone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one