Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

Abstract

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-␤ protein (A␤), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor B (NF-B). A␤-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-B activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of A␤, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses

“…However, the sustained production of these same mediators can also negatively impact cellular survival as demonstrated by others (31)(32)(33)(34)(35)(36). Based on the fact that proinflammatory mediator expression continues during the later stages of brain abscess in the face of relatively few surviving bacteria (22), we propose that this persistent cytokine response is deleterious, possibly confounding disease through the exaggerated destruction of normal brain parenchyma surrounding the abscess.…”

Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: A potential modulator of Fas-mediated apoptosis

“…Apaf-1, together with cytochrome C and caspase-9, forms the apoptosome, which is an essential component of mitochondrion-dependent apoptosis (Chen and Wang, 2002). Apaf-1 has been shown to mediate neuronal apoptosis in cultured cells exposed to beta amyloid or endoplasmic reticulum (ER) stress (Li et al, 2004;Smith and Deshmukh, 2007) and also in various animal models of nervous system diseases such as traumatic spinal cord injury, Parkinson's disease, and transient cerebral ischemia (Springer et al, 1999;Mochizuki et al, 2001;Cao et al, 2002). TIMP-3 can act as a pro-apoptotic protein in cancer cell lines, possibly through stabilization of death receptors and protection against proteolytic cleavage by metalloproteinases (Ahonen et al, 2003).…”

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

“…TNF-␣ is one of the key regulators of inflammation in different neuroinflammatory disorders including stroke, multiple sclerosis, Alzheimer's disease, and HAD (67)(68)(69)(70). Although TNF-␣ is chiefly known for its neurotoxic effects (62,63), several reports have also shown a neuroprotective role for this cytokine, including protection against excitotoxicity, glucose deprivation, and ␤-amyloid toxicity (64 -66).…”