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.
View: Text | PDF
Research Article Article has an altmetric score of 6

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

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

×

Figure 1

Engineering and testing of the IL-1βXAT mouse.

Options: View larger image (or click on image) Download as PowerPoint
Engineering and testing of the IL-1βXAT mouse. (A) The 2...
(A) The 293GLVP/CrePr stable cell line was transiently transfected with CMV/IL-1βXAT and cultured with or without RU486. RU486 caused DNA excision and expression of hIL-1β and β-galactosidase by RT-PCR and X-gal histochemistry, respectively. (B) The linear IL-1βXAT construct (~10 kb) consisted of a murine GFAP promoter; a transcriptional stop element flanked by loxP sequences; downstream ssIL-1β cDNA (11); and an internal ribosome entry site (IRES) followed by the β-gal coding sequence (LacZ) and bovine growth hormone polyadenylation signal (pA). Exposure to Cre recombinase caused excision of the transcriptional stop and subsequent transcriptional activation of ssIL-1β. (C) PCR screening of the 11 live-born IL-1βXAT pups using ssIL-1β–specific primers. Transgenic founder lines A/a and B/b are shown. (D) ELISA quantification (mean ± SEM) of hIL-1β protein supernatant concentration in individual primary astrocyte (n = 4) cultures from B/b and WT astrocytes transduced with FIV-Cre or FIV-GFP. ND, not detected (i.e., below detection limits). (E) The epicenter of viral transduction, the dentate gyrus, was bounded by NeuN-positive neurons (red stain). Colocalization of the epitope tag V5 (green stain) expressed by FIV-Cre demonstrated transduction of both neuronal (arrows) and non-neuronal cells (arrowheads). (F) Demonstration of hIL-1β expression (green stain) by astrocytes (red stain) in the dentate gyrus. Hoechst (blue stain) labeled cell nuclei. (G) MHC class II–stained coronal section from a B/b animal 1 week after intrahippocampal FIV-Cre injection (right hemisphere). Scale bars: 25 μm (E); 10 μm (F); 1 μm (G).