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Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal ?-catenin pathway function in an Alzheimer's disease model.

ABSTRACT: Inflammation is a key pathological hallmark of Alzheimer's disease (AD), although its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, IL-1? in particular has been implicated in playing a pathogenic role. In this study, we sought to investigate whether inhibition of IL-1? signaling provides disease-modifying benefits in an AD mouse model and, if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1R blocking Ab significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-?. Alterations in inflammatory responses correspond to reduced NF-?B activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3?, and p38-MAPK, and also reduces phosphorylated tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/?-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3? activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.

SUBMITTER: Kitazawa M

PROVIDER: S-EPMC4072218 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model.

Kitazawa Masashi M Cheng David D Tsukamoto Michelle R MR Koike Maya A MA Wes Paul D PD Vasilevko Vitaly V Cribbs David H DH LaFerla Frank M FM

Journal of immunology (Baltimore, Md. : 1950) 20111116 12

Inflammation is a key pathological hallmark of Alzheimer's disease (AD), although its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, IL-1β in particular has been implicated in playing a pathogenic role. In this study, we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model and, if so, by what molecular mechanisms. We report that c ...[more]

PMID: 22095718

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Project description:BackgroundDespite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss. MicroRNA (miRNA) deregulation is well established in AD brain but it is unclear whether Aβ or TAU pathology drives those alterations and whether miRNA changes contribute to cognitive decline.MethodsmiRNAseq was performed on cognitively intact (4 months) and impaired (10 months) male APPtg (APPswe/PS1L166P) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt). We analyzed the hippocampi of 12 mice per experimental group (n = 96 in total), and employed a 2-way linear model to extract differentially expressed miRNAs. Results were confirmed by qPCR in a separate cohort of 4 M and 10 M APPtg and APPwt mice (n = 7-9 per group) and in human sporadic AD and non-demented control brain. Fluorescent in situ hybridization identified their cellular expression. Functional annotation of predicted targets was performed using GO enrichment. Behavior of wild-type mice was assessed after intracerebroventricular infusion of miRNA mimics.ResultsSix miRNAs (miR-10a-5p, miR-142a-5p, miR-146a-5p, miR-155-5p, miR-211-5p, miR-455-5p) are commonly upregulated between APPtg and TAUtg mice, and four of these (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) are altered in AD patients. All 6 miRNAs are strongly enriched in neurons. Upregulating these miRNAs in wild-type mice is however not causing AD-related cognitive disturbances.ConclusionDiverging AD-related neuropathologies induce common disturbances in the expression of neuronal miRNAs. 4 of these miRNAs are also upregulated in AD patients. Therefore these 4 miRNAs (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) appear part of a core pathological process in AD patients and APPtg and TAUtg mice. They are however not causing cognitive disturbances in wild-type mice. As some of these miRNA target AD relevant proteins, they may be, in contrast, part of a protective response in AD.

Dataset Information

Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal ?-catenin pathway function in an Alzheimer's disease model.

Publications

Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model.

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