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CELLULAR AND MOLECULAR

The Cytoplasmic Domain of Alzheimer's Amyloid- Protein Precursor Causes Sustained Apoptosis Signal-Regulating Kinase 1/c-Jun NH₂-Terminal Kinase-Mediated Neurotoxic Signal via Dimerization

Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Medical Research Center, Tokyo, Japan (Y.H., T.N., T.C., E.T., Y.Y., M.I., M.Y., M.N., K.T., S.A., I.N.); and Division of Molecular Signal Transduction Research, Department of Medical and Dental General Research, Tokyo Medical and Dental University (H.K., H.N., H.I.) Tokyo, Japan

The biological function of full-length amyloid- protein precursor (APP), the precursor of A, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface APP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of APP (APP_CD) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with APP_CD (EGFR/APP 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 -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/APP hybrid. ASK1 formed a complex with APP_CD via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/APP 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 APP_CD 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 APP, which allows for the achievement of cell death by short-term anti-APP antibody treatment. Understanding the function of APP_CD and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.

Address correspondence to: Dr. Ikuo Nishimoto, Department of Pharmacology, KEIO University School of Medicine, Medical Research Center, 6th Floor, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: nisimoto{at}sc.itc.keio.ac.jp

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