Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal

Tang, Sung‐Chun; Lathia, Justin D.; Selvaraj, Pradeep K.; Jo, Dong Gyu; Mughal, Mohamed R.; Cheng, Ann‐Lii; Siler, Dominic A.; Markesbery, William R.; Arumugam, Thiruma V.; Mattson, Mark P.

doi:10.1016/j.expneurol.2008.05.014

Cited by 226 publications

(179 citation statements)

References 57 publications

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“…TLR4 signaling is required for efficient microglial clearance of Ab deposits in the mouse brain (51) and is also involved in Abinduced neuronal cell death (52). Both CD36-induced TLR4-TLR6 heterodimer formation (53) and TLR2 activation (27,54) have also been implicated in the response to Ab.…”

Section: Discussionmentioning

confidence: 99%

IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction

Westwell‐Roper

Dai

Soukhatcheva

et al. 2011

The Journal of Immunology

177

194

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Islets from patients with type 2 diabetes exhibit β cell dysfunction, amyloid deposition, macrophage infiltration, and increased expression of proinflammatory cytokines and chemokines. We sought to determine whether human islet amyloid polypeptide (hIAPP), the main component of islet amyloid, might contribute to islet inflammation by recruiting and activating macrophages. Early aggregates of hIAPP, but not nonamyloidogenic rodent islet amyloid polypeptide, caused release of CCL2 and CXCL1 by islets and induced secretion of TNF-α, IL-1α, IL-1β, CCL2, CCL3, CXCL1, CXCL2, and CXCL10 by C57BL/6 bone marrow-derived macrophages. hIAPP-induced TNF-α secretion was markedly diminished in MyD88-, but not TLR2- or TLR4-deficient macrophages, and in cells treated with the IL-1R antagonist (IL-1Ra) anakinra. To determine the significance of IL-1 signaling in hIAPP-induced pancreatic islet dysfunction, islets from wild-type or hIAPP-expressing transgenic mice were transplanted into diabetic NOD/SCID recipients implanted with mini-osmotic pumps containing IL-1Ra (50 mg/kg/d) or saline. IL-1Ra significantly improved the impairment in glucose tolerance observed in recipients of transgenic grafts 8 wk following transplantation. Islet grafts expressing hIAPP contained amyloid deposits in close association with F4/80-expressing macrophages. Transgenic grafts contained 50% more macrophages than wild-type grafts, an effect that was inhibited by IL-1Ra. Our results suggest that hIAPP-induced islet chemokine secretion promotes macrophage recruitment and that IL-1R/MyD88, but not TLR2 or TLR4 signaling is required for maximal macrophage responsiveness to prefibrillar hIAPP. These data raise the possibility that islet amyloid-induced inflammation contributes to β cell dysfunction in type 2 diabetes and islet transplantation.

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Section: Discussionmentioning

confidence: 99%

IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction

Westwell‐Roper

Dai

Soukhatcheva

et al. 2011

The Journal of Immunology

177

194

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“…For instance, TLR8 is expressed in neurons, and its activation promotes neuronal cell death in vitro (42). Conversely, reduced TLR4 activity protects cultured neurons from A␤ toxicity (43,44). However, whether TLRs play a role in age-dependent neurodegeneration in vivo is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia

Ahmad

Sweeney

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

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Frontotemporal dementia (FTD) is the most common form of dementia before 60 years of age. Rare pathogenic mutations in CHMP2B, which encodes a component of the endosomal sorting complex required for transport (ESCRT-III), are associated with FTD linked to chromosome 3 (FTD3). Animal models of FTD3 have not yet been reported, and what signaling pathways are misregulated by mutant CHMP2B in vivo is unknown. Here we report the establishment of a Drosophila model of FTD3 and show the genetic interactions between mutant CHMP2B and other components of ESCRT. Through an unbiased genome-wide screen, we identified 29 modifier loci and found that serpin5 (Spn5), a largely uncharacterized serine protease inhibitor, suppresses the melanization phenotype induced by mutant CHMP2B in the fly eye. We also found that Spn5 is a negative regulator of the Toll pathway and functions extracellularly, likely by blocking the proteolytic activation of Spaetzle, the Toll receptor ligand. Moreover, Spn5 inhibited activation of the Toll pathway by mutant CHMP2B. Our findings identify Spn5 as a regulator of the Toll pathway and CHMP2B toxicity and show that the Toll pathway is a major signaling pathway misregulated by mutant CHMP2B in vivo. This fly model will be useful to further dissect genetic pathways that are potentially relevant to the pathogenesis and treatment of FTD.Drosophila ͉ endosomal sorting complex required for transport (ESCRT) ͉ neurodegeneration ͉ modifier screen F rontotemporal dementia (FTD), a major clinical syndrome of frontotemporal lobar degeneration (FTLD), is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes (1, 2). Although FTD is the most common form of senile dementia in people under 60 years of age, the molecular pathogenesis remains poorly understood (3). In some FTD brains, tau neurofibrillary tangles are present in diseased neurons, and some tau mutations are indeed pathogenic (4, 5). Several new genes have been implicated in FTD with tau-negative pathology, including those encoding valosin-containing protein (VCP) (6), CHMP2B (7), progranulin (8, 9), and TDP-43 (10, 11). The molecular pathways affected by these mutations and how they contribute to disease progression remain unclear.Although dominantly inherited CHMP2B mutations associated with FTD linked to chromosome 3 (FTD3) are rare (7,12,13), studies of CHMP2B neurotoxicity in cell culture models have been informative. CHMP2B is the ortholog of the yeast protein Vps2, a component of the endosomal sorting complex required for transport (ESCRT-III), which is involved in the biogenesis of multivesicular bodies and other biological processes (14). In undifferentiated PC12 cells, ectopic overexpression of CHMP2B Intron5 , a mutant form of CHMP2B missing 35 aa at the C terminus, led to the accumulation of vesicular structures (7). In cultured rodent cortical neurons and other cell types, CHMP2B Intron5 caused dendritic retraction, autophagosome accumulation, and neuronal cell loss (15,16). At the mol...

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“…Interestingly, microglia activation due to LPS administration seems to mimic some features of AD such as increased Ab levels [14], suggesting that TLR4 very likely plays a role in extracellular Ab uptake. In fact, TLR4 expression increases in neurons when exposed to Ab42 [67] and, furthermore, a TLR4-attenuated polymorphism has been associated with protection against lateonset AD development [68]. Therefore, an initial accumulation of extracellular Ab could also be a pathogenic signal, as proposed in the amyloid cascade hypothesis [3].…”

Section: Hypothesis: the Role Of Ecsit As A Double-edge Sword In Ad Pmentioning

confidence: 99%

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

et al. 2012

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Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer's disease (AD). Based on the analysis of our AD‐associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid‐beta or oxidative damage. This converges into a complex cascade of patho‐physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro‐apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD.Editor's suggested further reading in BioEssays Binding of amyloid peptides to domain‐swapped dimers of other amyloid‐forming protein may prevent their neurotoxicity AbstractPlease, also watch the Video Abstract

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Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal

Cited by 226 publications

References 57 publications

IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction

IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction

Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

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