Tumor Necrosis Factor-α, Interleukin-1β, and Interferon-γ Stimulate γ-Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway

Liao, Yung-Feng; Wang, Bo-Jeng; Cheng, Hui-Ting; Kuo, Lan-Hsin; Wolfe, Michael S.

doi:10.1074/jbc.m402034200

Cited by 332 publications

(283 citation statements)

References 52 publications

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“…4A), similar to that specific for APP-C99 (35). T-Rex HeLa cells constitutively expressing the tetracycline repressor protein (tetR) were co-transfected with pGL4.31, a plasmid encoding a Gal4-driven luciferase reporter gene and either with a plasmid encoding a tetracyclinedriven FL-NRXN3␤ fused to the Gal4 DNA binding domain and to the VP16 activation domain (NRXN3␤-GV) or encoding the C-terminal APP fragment fused to Gal4-VP16 (APP-C99-GV).…”

Section: Nrxn3␤ Is Sequentiallymentioning

confidence: 99%

“…The NRXN3␤-GV-encoding sequence was then inserted into the pcDNA transmembrane 5/TO vector (Invitrogen), and its expression was placed under the control of two tetracycline operator sequences (TO). The APP-C99-GV construct was a gift from M. Wolfe (35). The luciferase reporter vector pLG4.31 (Promega) contains the synthetic firefly luciferase gene (luc 2) placed under the control of the GAL4UAS response element.…”

Section: Methodsmentioning

confidence: 99%

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Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Bot

Schweizer

Halima³

et al. 2011

Journal of Biological Chemistry

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Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that ␣-and ␥-secretases can sequentially process NRXN3␤, leading to the formation of two final products, an ϳ80-kDa N-terminal extracellular domain of Neurexin-3␤ (sNRXN3␤) and an ϳ12-kDa C-terminal intracellular NRXN3␤ domain (NRXN3␤-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the ␥-secretase that cause early-onset familial Alzheimer disease.

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Section: Nrxn3␤ Is Sequentiallymentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Bot

Schweizer

Halima³

et al. 2011

Journal of Biological Chemistry

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“…Our data also fit with recent findings showing that the phenotype of accumulating microglia changes as AD-like pathology progresses in tgAPP-PS1 mice (Hickman et al, 2008), from a protective, A␤-clearing role during early phases to an enhanced production in inflammatory cytokine and loss in A␤-clearing capabilities during later disease phases. Furthermore, it is conceivable that, in addition to dysfunctional Reelin signaling, proinflammatory cytokines including interferon-␥, TNF-␣ (tumor necrosis factor-␣), and interleukin-1, shown to be secreted from glia (Hickman et al, 2008) and demonstrated to be involved in ␤-secretase upregulation (Yamamoto et al, 2007) and ␥-secretase-mediated APP cleavage (Liao et al, 2004), contribute to A␤ production and accumulation.…”

Section: Discussionmentioning

confidence: 99%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

110

102

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In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

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“…For example, Rac1, as well as other small G proteins, has been implicated in the pathways triggered by inflammatory mediators, such as interleukin (IL)-1␤, IL-6, or tumor necrosis factor-␣, and by growth factors, such as transforming growth factor-␤ or platelet-derived growth factor, that have been found to be up-regulated in AD brains (24,25). These signaling pathways have been shown to stimulate the generation of A␤ (26). The involvement of Rac1 in AD is further stressed by the observation that an up-regulation of neuronal Cdc42/Rac1 occurs in selected neuronal populations of the AD brain in comparison with age-matched controls (27).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

RAC1 Inhibition Targets Amyloid Precursor Protein Processing by γ-Secretase and Decreases Aβ Production in Vitro and in Vivo

Désiré

Bourdin

Loiseau

et al. 2005

Journal of Biological Chemistry

126

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␤-Amyloid peptides (A␤) that form the senile plaques of Alzheimer disease consist mainly of 40-and 42-amino acid (A␤ 40 and A␤ 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of A␤ involves ␤-secretase and ␥-secretase activities and is regulated by membrane trafficking of the proteins involved in A␤ production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks A␤ 40 and A␤ 42 production but does not impact sAPP␣ levels and does not inhibit ␤-secretase. Rather, EHT 1864 modulates APP processing at the level of ␥-secretase to prevent A␤ 40 and A␤ 42 generation. This effect does not result from a direct inhibition of the ␥-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces A␤ 40 and A␤ 42 levels in guinea pig brains at a threshold that is compatible with delaying plaque accumulation and/or clearing the existing plaque in brain. EHT 1864 is the first derivative of a new chemical series that consists of candidates for inhibiting A␤ formation in the brain of AD patients. Our findings represent the first pharmacological validation of Rac1 signaling as a target for developing novel therapies for Alzheimer disease. Alzheimer disease (AD)2 is the most common neurodegenerative disorder marked by progressive loss of memory and cognitive ability. The pathology of AD is characterized by the presence of amyloid plaques (1), intracellular neurofibrillary tangles, and pronounced cell death. The ␤-amyloid peptide (A␤) (2) is the main constituent of senile plaques found in AD brains. Furthermore, extracellular A␤ 42 appears toxic to neurons in vitro and in vivo (reviewed in Ref.3). A␤ is generated by proteolysis of an integral membrane protein, the amyloid precursor protein (APP), via at least two post-translational pathways. The amyloidogenic cleavage of APP is a sequential processing of APP initiated by ␤-secretase (BACE), which cleaves APP within the luminal domain or at the cell surface, generating the N terminus of A␤ (4). This cleavage generates several membrane-bound proteolytic C-terminal fragments (CTFs), such as the 99-residue ␤-CTF (also called C99), as well as the secreted APP ectodomain sAPP␤. The C terminus of A␤ is subsequently generated by intramembranous cleavage of CTFs by ␥-secretase, producing either A␤ 40 or A␤ 42. The cleavages at residues 40 -42 are referred to as ␥-cleavage, and the cleavages at residues 49 -52 are referred to as ⑀-cleavage (5). The nonamyloidogenic cleavage of APP, which precludes A␤ generation, is mediated by ␣-secretase, a disintegrin and metalloproteinase 10, and a disintegrin and metalloproteinase 17, in a reaction believed to occur primarily on the plasma membrane. This proteolytic cleavage by ␣-secretase occurs within the A␤ region and produces soluble APP (sAPP␣), the dominant processing product, and the residual membrane-bound 10-kDa CTF (CTF␣, also called C83). Like C99, C83 is a subs...

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Tumor Necrosis Factor-α, Interleukin-1β, and Interferon-γ Stimulate γ-Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway

Cited by 332 publications

References 52 publications

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

RAC1 Inhibition Targets Amyloid Precursor Protein Processing by γ-Secretase and Decreases Aβ Production in Vitro and in Vivo

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