Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4210-5. Epub 2004 Mar 8.

Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons.

Author information

1
Department of Pathology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.

Abstract

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.

PMID:
15007167
PMCID:
PMC384720
DOI:
10.1073/pnas.0307349101
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center