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. 2004 Nov;165(5):1643-52.
doi: 10.1016/S0002-9440(10)63421-9.

Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein

Arianna Bellucci  1 , Andrew J Westwood, Esther Ingram, Fiorella Casamenti, Michel Goedert, Maria Grazia Spillantini
Affiliations

Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein

Arianna Bellucci et al. Am J Pathol. 2004 Nov.

Abstract

Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and neurodegeneration leading to nerve cell loss. At 5 months of age, the pathological changes are most marked in brainstem and spinal cord. Here we show that these changes are accompanied by marked neuroinflammation. Many tau-positive nerve cells in brainstem and spinal cord were strongly immunoreactive for interleukin-1beta and cyclooxygenase-2, indicating induction and overproduction of proinflammatory cytokines and enzymes. In parallel, numerous activated microglial cells were present throughout brain and spinal cord of transgenic mice, where they concentrated around tau-positive nerve cells. These findings suggest that inflammation may play a significant role in the events leading to neurodegeneration in the tauopathies and that anti-inflammatory compounds may have therapeutic potential.

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Figures

Figure 1
Figure 1
IL-1β immunoreactivity in brainstem and spinal cord of human P301S tau transgenic mice and age-matched controls. A and B: Brainstem of 5-month-old transgenic (A) and control (B) mice. C and D: Spinal cords of 5-month-old transgenic (C) and control (D) mice. Note the strong staining of some nerve cell bodies and processes (arrows in C). Scale bars: 150 μm (B, also representative for A); 71 μm (D, also representative for C).
Figure 2
Figure 2
COX-2 immunoreactivity in brain and spinal cord of human P301S tau transgenic mice. Strongly stained nerve cells and processes (arrows) in brainstem (A), spinal cord (C), cerebral cortex (D), hippocampus (E), and cerebellum (F) of 5-month-old human P301S tau transgenic mice. B: COX-2 immunoreactivity in brainstem of an age-matched control mouse. Note the strong staining of some nerve cell bodies and processes in A, C, D–F. Scale bars: 150 μm (B, also representative for A); 85 μm (C); 80 μm (D); 170 μm (E); 70 μm (F).
Figure 3
Figure 3
Double-labeling immunofluorescence staining for IL-1β (green) and tau phosphorylated at S202 and T205 (antibody AT8) (red) in brainstem and spinal cord of human P301S tau transgenic mice. A and B: Brainstem stained for IL-1β (A) and phosphorylated tau (B). C: Merged images shown in A and B. D and E: Spinal cord stained for IL-1β (D) and phosphorylated tau (E). F: Merged images shown in D and E. Co-localization is indicated by the yellow color. Scale bars: 60 μm (C, also representative for A, B); 125 μm (F, also representative for D, E).
Figure 4
Figure 4
Double-labeling immunofluorescence staining for COX-2 (green) and tau phosphorylated at S202 and T205 (antibody AT8) (red) in brainstem and spinal cord of human P301S tau transgenic mice. A and B: Brainstem stained for COX-2 (A) and phosphorylated tau (B). C: Merged images shown in A and B. D and E: Spinal cord stained for COX-2 (D) and phosphorylated tau (E). F: Merged images shown in D and E. Co-localization is indicated by the yellow color. Scale bars: 45 μm (C, also representative for A, B); 40 μm (F, also representative for D, E).
Figure 5
Figure 5
Immunoblotting for IL-1β and COX-2 of spinal cord (left) and brainstem (right) from three human P301S tau transgenic mice and three age-matched controls. Immunoblotting for actin was used to ensure equal loading. Note the increased levels of proIL-1β, IL-1β and COX-2 in tissues from the transgenic mice.
Figure 6
Figure 6
Double-labeling immunostaining for OX-42 or OX-6 (brown) and tau phosphorylated at S422 (antibody AP422) (red) in brainstem and spinal cord of human P301S tau transgenic mice and age-matched controls. A, B, and E: Brainstem of transgenic (A, E) and control (B) mice. C, D, and F: Spinal cord of transgenic (C, F) and control mice (D). Sections A to E were stained for OX-42 and phosphorylated tau. Section F was stained for OX-6 and phosphorylated tau. Scale bars: 70 μm (B, also representative for A); 90 μm (D, also representative for C); 60 μm (E, F).
Figure 7
Figure 7
Major histocompatibility class II-immunoreactivity (antibody M5/114.15.2) in spinal cord of mice transgenic for human wild-type tau, human P301S tau, and age-matched controls. A and B: Five-month-old mouse transgenic for human P301S tau (A) and age-matched control (B). C and D: Fourteen-month-old mouse transgenic for human wild-type tau (C) and age-matched control (D). Scale bars: 50 μm (D, also representative for A–C). Note the staining of cells with the morphology of activated microglial cells in A.
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