Association of interleukin-1 gene polymorphisms with Alzheimer's disease

Nicoll, James A. R.; Mrak, Robert E.; Graham, David I.; Stewart, Jennifer; Wilcock, Gordon; Macgowan, SH; Esiri, Margaret M.; Murray, Lilian S.; Dewar, Deborah; Love, Seth; Moss, T. H.; Griffin, W. Sue T.

doi:10.1002/1531-8249(200003)47:3<365::aid-ana13>3.0.co;2-g

Cited by 328 publications

(112 citation statements)

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“…Human gene polymorphism and promoter studies suggest a relationship between IL-1b, ACT, and AD (Akiyama et al, 2000;Nicoll et al, 2000). The common TT IL-1b polymorphism, which shows higher plasma IL-1b levels in AD patients, interacts with one polymorphism in ACT to significantly increase AD risk (Licastro et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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Section: Discussionmentioning

confidence: 99%

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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“…[132][133][134][135][136][137] Importantly, in another of study of living AD patients, a -889 polymorphism in IL1A was associated not only with increased an risk for AD (4.5 times) but also with earlier disease onset (seven to nine years earlier). 134 Although the numbers of studies supporting such an association is increasing, a few studies have failed to substantiate this.…”

Section: Interleukin-1mentioning

confidence: 94%

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Griffin¹,

Barger²

2010

US Neurology

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This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis wasproposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each. KeywordsAlzheimer's disease (AD), amyloid β (Aβ), apolipoprotein E (ApoE), β−amyloid precursor protein (βAPP), cytokines, Down syndrome (DS), excitotoxicity, glutamate, interleukin-1 (IL-1), S100B, tumor necrosis factor alpha (TNFα) Disclosure: The authors have no conflicts of interest to declare. Acknowledgments:Much of the work cited in this article was supported by National Institutes of Health (NIH) grants P01AG12411 (to WSTG) and R01AG17498 (to SWB). The authors thank Orwa Aboud, MD, for helpful comments and editing. A progression of these neuropathological events seems apparent. For example, the plethora of Aβ plaques at end stages-from several to many-and an inclusion of neurofibrillary tangles-in a few to numerous neurons-strongly suggests that these neuropathological Received

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“…Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the amyloidogenic Aβ 1-42 [18,76].…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

192

142

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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Association of interleukin-1 gene polymorphisms with Alzheimer's disease

Cited by 328 publications

References 20 publications

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

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