The cytoplasmic domain of Alzheimer's amyloid-β protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH 2-terminal kinase-mediated neurotoxic signal via dimerization

Yuichi Hashimoto, Takako Niikura, Tomohiro Chiba, Emi Tsukamoto, Hisae Kadowaki, Hideki Nishitoh, Yohichi Yamagishi, Miho Ishizaka, Marina Yamada, Mikiro Nawa, Kenzo Terashita, Sadakazu Aiso, Hidenori Ichijo, Ikuo Nishimoto

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)889-902
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume306
Issue number3
DOIs
Publication statusPublished - 2003 Sep 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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