Abstract
The biological function of full-length amyloid-β protein precursor (AβPP), the precursor of Aβ, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface AβPP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of AβPP (AβPPCD) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with AβPPCD (EGFR/AβPP 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 α-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/AβPP hybrid. ASK1 formed a complex with AβPPCD via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/AβPP 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 AβPPCD 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 AβPP, which allows for the achievement of cell death by short-term anti-AβPP antibody treatment. Understanding the function of AβPPCD and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.
Footnotes
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This work was supported in part by grants from Japan Research Foundation for Clinical Pharmacology (Y.H.) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.051383.
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ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid-β; AβPP, Aβ protein precursor; PTX, pertussis toxin; CD, cytoplasmic domain; mDab1, mouse disabled 1; JNK, c-Jun N-terminal kinase; JIP-1b, JNK-interacting protein-1b; EGF, epidermal growth factor; EGFR, receptor for EGF; ED, extracellular domain; ASK1, apoptosis signal-regulating kinase 1; wt, wild-type; PCR, polymerase chain reaction; dn, dominant-negative; ca, constitutively active; HA, hemagglutinin; GEE, glutathione-ethyl ester; l-NMMA, NG-monomethyl-l-arginine monoacetate salt; SP600125, anthra[1,9-cd]pyrazol-6(2H)-one; PD98059, 2′-amino-3′-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; DEVD, Ac-DEVD-CHO (acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-aldehyde); APO, apocynin (4-hydroxy-3-methoxyacetophenone); FBS, fetal bovine serum; αSYN, α-synuclein; HRP, horseradish peroxidase; PAGE, polyacrylamide gel electrophoresis; DMEM-N2, Dulbecco's modified Eagle's medium containing N2 supplement; HN, humanin; PS, presenilin.
- Received March 7, 2003.
- Accepted May 27, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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