Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid- Protein-Induced Neuron Death (original) (raw)
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The Journal of Neuroscience, 2004
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-β protein (Aβ), 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 κB (NF-κB). Aβ-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-κB 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 o...
The Induction of the TNF Death Domain Signaling Pathway in Alzheimer's Disease Brain
Neurochemical Research, 2003
The tumor necrosis factor-α death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-α (TNFα), TNF receptor type 1 (TNF-R1), TNF receptor–associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1β–converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.
Inhibition of NF- B potentiates amyloid -mediated neuronal apoptosis
Proceedings of the National Academy of Sciences, 1999
One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid  peptide (A) neurotoxicity. A elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously we reported that NF-B is activated by low doses of A only. Here we show that NF-B activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 M A-(1-40) protects against neuronal death induced with 10 M A-(1-40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor ␣ (TNF-␣).
TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
Acta Neuropathologica Communications, 2021
The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 a...
Inhibition of NF-kappa B Potentiates Amyloid beta -Mediated Neuronal Apoptosis
Proceedings of the National Academy of Sciences of the United States of America, 1999
One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid  peptide (A) neurotoxicity. A elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously we reported that NF-B is activated by low doses of A only. Here we show that NF-B activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 M A-(1-40) protects against neuronal death induced with 10 M A-(1-40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor ␣ (TNF-␣). Maximal activation of NF-B was found with 2 ng͞ml TNF-␣. Pretreatment with TNF-␣ protected cerebellar granule cells from cell death induced by 10 M A-(1-40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-B-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-B activation. Overexpression of a transdominant negative IB-␣ blocks NF-B activation and potentiates Amediated neuronal apoptosis. Our findings show that activation of NF-B is the underlying mechanism of the neuroprotective effect of low-dose A and TNF-␣. In accordance with these in vitro data we find that nuclear NF-B immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls. Taken together these data suggest that pharmacological NF-B activation may be a useful approach in the treatment of AD and related neurodegenerative disorders. Alzheimer's disease (AD) is characterized by plaques within many brain regions, including the cerebellum (1). The major component of plaques is an amyloid peptide named A4 or A (2). A is a proteolytic product of the larger amyloid precursor protein (APP; ref. 3). Further pathological criteria are the formation of neurofibrillary tangles (4) or increased advanced glycation end products (5), which also can activate NF-B (6). Mutations in the presenilin genes 1 and 2 (for review see ref. 7) were described, which can lead to increased production of A in transgenic mice (8). Mutant presenilin proteins interact directly with APP (9). Activation of NF-B protects against the proapoptotic action of mutated presenilin-1 (10). Knockout of APP results in agenesis of corpus callosum, memory defects, and reactive gliosis (11, 12). An important mechanism leading to neurodegeneration during AD is A neurotoxicity (13). Two dose-dependent effects of A were described: a low neurotrophic dose and a high neurotoxic dose (13). Previously we reported that NF-B is activated only by low doses of A in cerebellar granule cells (14). Similarly A could activate
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, but their roles in the brain remain unclear. Here we present a novel interaction between TNFR subtypes and TNF-alpha in the brain. Our studies on target-depleted TNFR in mice show that TNF-alpha has little effect on hippocampal neurons in which TNFRI, containing an "intracellular death domain," is absent (TNFRI -/-), whereas neurons from TNFRII knock-out mice are vulnerable to TNF-alpha even at low doses. Moreover, little nuclear factor-kappaB (NF-kappaB) translocation is induced by TNF-alpha in neurons of TNFRI -/-, whereas NF-kappaB subunit p65 is still translocated from the cytoplasm into the nucleus in neurons from wild-type and TNFRII -/- mice. Furthermore, p38 mitogen-activated protein (MAP) kinase activity is upregulated in neurons from both wild-type and TNFRI -/-, but no alteration of p38 MAP kinase was found in neurons from TNFRII. Results from overexpression of TNF re...
Cell Death and Disease, 2015
Abbreviations: Aβ, amyloid-β; AD, Alzheimer's disease; ADDL, Aβ-derived diffusible ligand; DR, death receptor; FAIM, Fas apoptotic inhibitory molecule; FAIM-L, long form of FAIM protein; FAIM-S, short form of FAIM protein; FLIP-L, FLICE-like inhibitory protein, long isoform; Lv, lentivirus; MAPK/ERK, mitogen-activated protein kinase/ extracellular-signal-regulated kinase; MCI, mild cognitive impairment; NFT, neurofibrillary tangles; NFκB, nuclear factor-κB; oAβ, oligomeric Aβ; PARP, poly (ADP-ribose) polymerase; PS1 M146L xAPP 751sl , Presenilin 1 with mutation M146L x human APP751 (Amyloid Precursor Protein) carrying the London (V717I) and the Swedish (K670N/ M671L) mutations; qPCR, quantitative PCR; RNAi, RNA interference; sc, scrambled; shRNA, short hairpin RNA; shFAIM-L, short hairpin RNA for FAIM-L; smFAIM-L, lentivirus that expresses FAIM-L with a silent mutation; SOM/NPY, somatostatin/neuropeptide Y; TNFα, tumor necrosis factor-α; TNFR1, TNF receptor 1 also called TNFRSF1A; WT, wild type