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Regulation of IL-1β-Induced Cyclooxygenase-2 Expression by Interactions of Aβ Peptide, Apolipoprotein E and Nitric Oxide in Human Neuroglioma

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Abstract

Alzheimer disease (AD) is characterized by chronic neuroinflammation, which may lead to dysfunction in neuronal circuits. Although reactive microglia are found in association with accumulation of beta amyloid (Aβ) plaques in the AD brain, their contribution to neuronal cell loss remains speculative. A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele, which has been shown to contribute significantly to neurodegeneration in AD. Many studies have documented the ability of Aβ fibrils in vitro to induce microglia to undergo phenotypic activation, which results in the secretion and/or expression of a plethora of free radicals and pro-inflammatory mediators. These mediators, such as reactive nitrogen/oxygen species and IL-1β as well as cyclooxygenase-2 (COX-2) with associated prostaglandin E2 (PGE2), are believed to be neurotoxic and to contribute to the underlying cause of AD. We have used the human H4 neuroglioma cells as a model astroglial system to examine the interactions between IL-1β and nitric oxide (NO) as co-stimulators of Aβ1–40 in enhancing the expression of COX-2 and production of PGE2 in the presence of recombinant human apolipoprotein E4 (apoE4). Neither Aβ1–40 nor its reverse sequence analog Aβ40–1 alone had a significant effect on COX-2 expression and PGE2 production in the cells. In contrast, after co-incubation with apoE4, Aβ1–40 increased IL-1β-induced COX-2 expression and PGE2 production. Aβ12–28, which binds with high affinity to apoE4, blocked apoE4-mediated effects on Aβ1–40. Furthermore, (±)-S-Nitroso-N-acetylpenicillamine (SNAP), an agent that releases nitric oxide (NO) in situ, alone did not affect IL-1β-induced COX-2 expression, but increased PGE2 production only. Addition of Aβ1–40 preincubated with apoE4 to H4 cells in the presence of SNAP led to an additive IL-1β-induced COX-2 expression and PGE2 production. These observations indicate that increased PGE2 resulted from increased nitrosative stress, which is enhanced by apoE4. Thus a molecular understanding of the interactions of apoE4 with Aβ, NO and IL-1β on the regulation of the COX-2/prostaglandin pathway may open new avenues in understanding the mechanism of development of neurodegenerative disease such as AD.

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Acknowledgements

The University of Missouri Research Board (UMRB) grant to OJI supported this project.

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  1. Division of Pharmacology and Toxicology, UMKC School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, HSB # 2247, Kansas City, MO, 64108, USA

    Orisa J. Igwe

  2. Astellas Pharma US Inc., Three Parkway North, Deerfield, IL, 60015, USA

    Anju S. Samy

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  1. Anju S. Samy
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  2. Orisa J. Igwe
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Correspondence to Orisa J. Igwe.

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Samy, A.S., Igwe, O.J. Regulation of IL-1β-Induced Cyclooxygenase-2 Expression by Interactions of Aβ Peptide, Apolipoprotein E and Nitric Oxide in Human Neuroglioma. J Mol Neurosci 47, 533–545 (2012). https://doi.org/10.1007/s12031-011-9670-8

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