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

Abstract

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

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

“…In accordance with the finding that the V642I-APP-induced death is mediated by a signaling pathway that involves JNK (37,38,43,44), exogenous expression of V642I-APP increased the level of phosphorylated JNK (p-JNK) (Fig. 8C, lane 5).…”

“…pcDNA3-FLAG-human JNK-1a1 (100% identical to mouse JNK1a1) was purchased from Addgene. Constitutively active (ca) JNK and caASK1-encoding vectors were as described previously (37,38). The mouse/rat (m/r) SH3BP5 cDNA was the mouse SH3BP5 cDNA in which three nucleotides of the mouse SH3BP5 siRNA-corresponding region were changed to the nucleotides of the rat SH3BP5 (A261T; A267G; A273G).…”

“…duced death is intracellularly mediated by apoptosis signal-stimulating kinase-1 (ASK1) and JNK (37,38,43,44). Given that Humanin also inhibits caASK1-and caJNK-triggered neuronal cell death (37, 38), we first examined whether expression of SH3BP5 prevents this cell death.…”

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

“…Combined with the reported studies, the molecular signaling mechanisms of HN-mediated neuroprotection include stimulation of the PI3 kinase/AKt pathway [56] , inhibition of pro-apoptotic Bcl-2 family members [57] , and modulation of the JAK/STAT pathways [58] by binding to a complex or complexes involving ciliary neurotrophic factor receptor, the IL-27receptor WSX-1, and gp130 [59] .…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…In in vitro studies, expression of familial Alzheimer's disease mutants of APP results in apoptotic neuronal injury [150]. It is the cytoplasmic domain of APP that can lead to sustained apoptosis through c-Jun N-terminal kinase pathways [85]. Additional studies have illustrated that direct application of Aβ to neuronal cells can lead to chromatin condensation, DNA fragmentation, and membrane PS exposure characteristic of apoptosis in cultured neurons (Fig.…”