Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction

Origlia, Nicola; Righi, Massimo; Capsoni, Simona; Cattaneo, Antonino; Fang, Fang; Stern, David M.; Chen, John Xi; Schmidt, Ann Marie; Arancio, Ottavio; Yan, Shirley ShiDu; Domenici, Luciano

doi:10.1523/jneurosci.0204-08.2008

Cited by 185 publications

(200 citation statements)

References 75 publications

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“…These observations agree with the concept that amyloid precursor proteins, not amyloid fibrils, cause organ dysfunction and contribute to the pathophysiology and progression in various amyloid-related diseases (7,8). Among the multiple key mediators involved in the regulation of redox status, stress-responsive p38 mitogen-activated protein kinases (MAPK) have been reported to be activated in other types of amyloid disease such as Alzheimer's disease (9)(10)(11)(12). Our prior findings have implicated oxidative stress in AL-LC-induced cellular dysfunction.…”

supporting

confidence: 86%

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Shi

Guan

Jiang

et al. 2010

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

281

201

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Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC–induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-β-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38α MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC–induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

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supporting

confidence: 86%

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Shi

Guan

Jiang

et al. 2010

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

281

201

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“…However, more recently, it has been appreciated that oligomeric and prefibrillar A␤ and A␤ have similar cytotoxic effects (34) and such soluble forms of A␤ are believed to play a critical role in the pathogenesis of AD. Recent work has demonstrated that oligomeric A␤ , at a concentration of 200 nM, is capable of blocking long-term potentiation at cortical synapses in the hippocampus and entorhinal cortex (10,28,35,36). Taken together, our findings suggest that via RAGE, neuronal transmembrane transport of A␤ and A␤ carries soluble assemblies of amyloid peptide into the cell.…”

Section: Discussionsupporting

confidence: 64%

“…In addition, Arancio et al (28) reported increased phosphorylation of CREB, ERK1/2, p38 MAPK, and CaMKII in hippocampal extracts from Tg mice overexpressing RAGE and mAPP. RAGE-dependent activation of p38 signal transduction also plays an important role in A␤-mediated synaptic failure (35,36). However, direct links between RAGE-mediated signaling pathways and A␤ neurotoxicity remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Takuma

Fang

Zhang

et al. 2009

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

269

216

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Intracellular amyloid-␤ peptide (A␤) has been implicated in neuronal death associated with Alzheimer's disease. Although A␤ is predominantly secreted into the extracellular space, mechanisms of A␤ transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of A␤ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human A␤ subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of A␤ and protection from A␤-mediated mitochondrial dysfunction. A␤ activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of A␤-RAGE complex. Similar intraneuronal co-localization of A␤ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of A␤ from the extracellular to the intracellular space, thereby enhancing A␤ cytotoxicity.is a progressive neurodegenerative process characterized by senile plaques, neurofibrillary tangles, and neuronal loss (1, 2). Deposition of amyloid-␤ peptide (A␤), a 39-43-amino acid peptide derived from the transmembrane amyloid precursor protein (APP), is found in extracellular senile plaque cores and is associated with neurodegeneration in later stages of AD. In contrast, recent studies suggest that accumulation of intraneuronal A␤ may be an early event in the pathogenesis of AD (3-16). Addition of A␤ to human neuronal-like cells caused significant mitochondrial damage (17). Furthermore, our recent study revealed that binding of A␤ to A␤-binding alcohol dehydrogenase (ABAD) or cyclophilin D (10, 11) intracellularly triggered events leading to neuronal apoptosis through a mitochondrial pathway (12,13,18,19). However, mechanisms through which A␤ produced at the plasma membrane and released into the extracellular space reaches the intracellular milieu remain to be elucidated.Receptor for advanced glycation end products (RAGE) is a multiligand receptor of the Ig superfamily of cell surface molecules (20)(21)(22). RAGE acts as a counter-receptor for several quite distinct classes of ligands, such as AGEs, S100/calgranulins, HMG1 (high mobility group 1 or amphoterin), and the family of crossed ␤-sheet fibrils/macromolecular assemblies, which activate receptormediated signal transduction pathways. These ligand-receptor interactions are believed to exert pathogenic effects through sustained cellular perturbation in a range of chronic disorders, including the secondary complications of diabetes, inflammation, and neurodegenerative processes (23,24). RAGE, a cell surface binding site for A␤ (25), is expressed at higher levels in an A␤-rich environment (...

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“…Finally, given that the inhibition of p38 activation is sufficient to prevent Aβ-induced neurotoxicity, as also observed by others [33,56] , atorvastatin treatment controls AβO-induced neurotoxicity through the regulation of p38MAPK phosphorylation. Activated p38MAPK is observed in human AD brain tissue [57] and in AD-relevant animal models [58,59] , and cell culture studies strongly implicate p38MAPK in the increased production of proinflammatory cytokines in the glia activated by Aβ [60] .…”

Section: Discussionsupporting

confidence: 61%

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

et al. 2014

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Aim: To investigate whether atorvastatin treatment could prevent Aβ 1-42 oligomer (AβO)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin. Methods: SD rats were injected with AβOs (5 nmol, icv). The rats were administrated with atorvastatin (10 mg·kg -1 ·d -1 , po) for 2 consecutive weeks (the first dose was given 5 d before AβOs injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD-95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with AβOs (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence. Results: The AβO-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 µmol/L) concentration-dependently attenuated the AβO-induced synaptotoxicity, including the loss of dendritic marker MAP-2, and synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 µmol/L) blocked the AβO-induced loss of synaptophysin and PSD-95. Conclusion: Atorvastatin prevents AβO-induced synaptotoxicity and memory dysfunction through a p38MAPK-dependent pathway.

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Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction

Cited by 185 publications

References 75 publications

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

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