Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation

Sheng, Jin; Jones, Richard A.; Zhou, Xue; McGinness, John M.; Eldik, Linda J. Van; Mrak, Robert E.; Griffin, W. Sue T.

doi:10.1016/s0197-0186(01)00041-9

Cited by 145 publications

(95 citation statements)

References 24 publications

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“…Furthermore, IL-1-treated rats exhibited significantly increased numbers of phosphorylated tau-containing neurons, and these neurons were also immunoreactive with phosphorylated p38 -MAPK (Sheng et al, 2001). It was also reported that JNK was markedly activated within 3 h of LPS injection in rats, and the activation of JNK was mediated by IL-1␤ (Lynch et al, 2004).…”

Section: Discussionmentioning

confidence: 89%

Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

Kitazawa¹,

Oddo²,

Yamasaki³

et al. 2005

J. Neurosci.

608

448

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Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD).Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloid ␤-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.

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Section: Discussionmentioning

confidence: 89%

Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

Kitazawa¹,

Oddo²,

Yamasaki³

et al. 2005

J. Neurosci.

608

448

View full text Add to dashboard Cite

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“…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] . The activation of p38MAPK in neuronal cells has been associated with IL-1 and hyperphosphorylated tau in AD [61] . Similar to several other members of the MAPK family, p38MAPK is activated by dual phosphorylation; cytokines, including IL-1 and TNF-α, can affect this activation.…”

Section: Discussionmentioning

confidence: 99%

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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“…Subsequent investigations suggest that the overexpressed IL-1 restrains the function of cholinergic systems [49] and favors the formation of Ab plaques and accumulation of NFTs [50,51], supporting the important role of IL-1 in AD development. This concept has been further supported by gene association analysis, as several variants located in the genes of IL-1A and IL-1B have been found to influence AD risk.…”

Section: Il-1mentioning

confidence: 99%

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

2016

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Neuroinflammatory processes are a central feature of Alzheimer's disease (AD) in which microglia are over-activated, resulting in the increased production of proinflammatory cytokines. Moreover, deficiencies in the antiinflammatory system may also contribute to neuroinflammation. Recently, advanced methods for the analysis of genetic polymorphisms have further supported the relationship between neuroinflammatory factors and AD risk because a series of polymorphisms in inflammation-related genes have been shown to be associated with AD. In this review, we summarize the polymorphisms of both pro-and anti-inflammatory cytokines related to AD, primarily interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, IL-4, IL-10, and transforming growth factor beta, as well as their functional activity in AD pathology. Exploration of the relationship between inflammatory cytokine polymorphisms and AD risk may facilitate our understanding of AD pathogenesis and contribute to improved treatment strategies.

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Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation

Cited by 145 publications

References 24 publications

Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease

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

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

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