Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons.
Tumor necrosis factor (TNF) alpha and mitogen-activated protein kinase/c-Jun N-terminal kinase (MAPK/JNK) pathways are both implicated in Alzheimer's disease (AD) pathogenesis. Increased expression of several members of the TNF pathway and JNK activation of c-Jun ultimately result in neuronal apoptosis. DENN/MADD, a multifunctional domain protein expressed in neurons, interacts with both the p55 TNF receptor (TNFR) type 1 and JNK3, placing it at a critical juncture in regulating signaling of neurodegeneration. We examined expression and interactions of the TNFR1 binding proteins, DENN/MADD, and TNFR-associated death domain (TRADD) protein in AD-affected tissues and cell cultures. We found reduced DENN/MADD and increased TRADD expression immunohistochemically in the hippocampus in areas of AD pathology compared to normal controls but little intraneuronal colocalization. In brain homogenates, DENN/MADD protein and mRNA expression was significantly reduced in AD compared to controls. Conversely, TRADD, TNFR1, and activated JNK were increased. Murine neuroblastoma and rat hippocampal cultures stressed with Abeta1-42 and the cortices of AD transgenic mice (Tg2576Swe) each showed decreased DENN/MADD expression and TRADD up-regulation in the mice, compared to controls. DENN/MADD antisense treatment of cultured rat hippocampal neurons reduced endogenous DENN/MADD and promoted neuronal cell death. DENN/MADD and TRADD competitively bound to TNFR1 when overexpressed in N(2)A cells, with DENN/MADD abrogating TNFR1 binding to TRADD. DENN/MADD may therefore be protective by inhibiting TRADD-induced apoptotic cell death. Reduction of DENN/MADD may affect long-term neuronal viability in AD by allowing TRADD mediation of TNFR1 signaling in response to oxidative or cytokine-promoted stresses.
Del Villar
Keith
K
Department of Pathology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Miller
Carol A
CA
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053418:Death Domain Receptor Signaling Adaptor Proteins; D015536:Down-Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; C491371:Madd protein, mouse; C491370:Madd protein, rat; D010455:Peptides; D018124:Receptors, Tumor Necrosis Factor