Tnfr1
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 N2A 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 [PubMed - as supplied by publisher]