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Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology
Solomon S. Shaftel, … , Renee E. Johnson, M. Kerry O’Banion
Solomon S. Shaftel, … , Renee E. Johnson, M. Kerry O’Banion
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1595-1604. https://doi.org/10.1172/JCI31450.
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Research Article Article has an altmetric score of 6

Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

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Abstract

Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1β has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1β overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1β overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (Aβ40) and Aβ42 decreased significantly. These results demonstrate a possible adaptive role for IL-1β–driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

Authors

Solomon S. Shaftel, Stephanos Kyrkanides, John A. Olschowka, Jen-nie H. Miller, Renee E. Johnson, M. Kerry O’Banion

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Figure 2

Induction of hIL-1β mediates a robust neuroinflammatory response in the mouse hippocampus.

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Induction of hIL-1β mediates a robust neuroinflammatory response in the ...
IL-1βXAT A/a and B/b mice and WT controls were injected unilaterally in the dentate gyrus with approximately 1.5 × 104 infectious units of FIV-Cre. Inflammatory indices were assayed 2 weeks later. (A) Microglial activation was demonstrated by increased staining intensity of Iba-1 (green) and MHC class II (red) in B/b and A/a relative to WT mice, with colocalization appearing yellow. Insets show higher-magnification morphologic changes among Iba-1–positive cells residing in the dentate gyrus. (B) Astrocyte activation, as evidenced by increased GFAP expression, was demonstrated in the dentate gyrus of B/b animals only. Scale bars: 50 μm (A and B); 10 μm (insets in A). (C and D) qRT-PCR analysis compared relative abundance of gene transcripts in ipsilateral (I) and contralateral (C) hippocampi. Analysis revealed significant upregulation of MHC class II in A/a and B/b mice (C), but significant upregulation of GFAP in B/b mice only (D), compared with WT controls. n = 3–4 per group. Data are mean ± SEM. *P < 0.05 versus respective WT.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 3 patents
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