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Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy

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ABSTRACT

The role of immune responses in the cognitive impairments associated with tauopathy is unclear. Laurent et al. identify a CD8+ T-cell infiltration in the hippocampus of THY-Tau22 transgenic mice. T-cell depletion reverses spatial memory deficits in these animals, supporting a role for hippocampal T-cell infiltration in tau-driven cognitive impairments.

No MeSH data available.


Related in: MedlinePlus

Age-dependent upsurge of chemokines in the hippocampus of THY-Tau22 mice. (A) Quanititative PCR analysis of Ccl3, Ccl4, Ccl5 and Cxcl5 mRNAs revealed a significant and generally progressive overexpression in the hippocampus of transgenic animals as compared to wild-type (WT). Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 5–13/group. (B) ELISA determinations of hippocampal CCL3, CCL4 and CCL5 levels in wild-type and THY-Tau22 mice at all ages. The three chemokines were found significantly increased in tau animals, CCL3 being the earliest upregulated chemokine. Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–8/group. (C) Immunofluorescence analysis of CCL3 expression in the hippocampus of THY-Tau22 mice and wild-type littermates at the age of 12 months. Labelling of CCL3 (red) with the microglial marker Iba1 or the astrocyte marker GFAP (green) revealed clustered CCL3 staining solely in Iba1-positive cells (arrowheads and inset) in transgenic tau mice. To a lesser extent, such clusters are present in wild-type animals. Scale bar = 20 µm.
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aww270-F2: Age-dependent upsurge of chemokines in the hippocampus of THY-Tau22 mice. (A) Quanititative PCR analysis of Ccl3, Ccl4, Ccl5 and Cxcl5 mRNAs revealed a significant and generally progressive overexpression in the hippocampus of transgenic animals as compared to wild-type (WT). Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 5–13/group. (B) ELISA determinations of hippocampal CCL3, CCL4 and CCL5 levels in wild-type and THY-Tau22 mice at all ages. The three chemokines were found significantly increased in tau animals, CCL3 being the earliest upregulated chemokine. Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–8/group. (C) Immunofluorescence analysis of CCL3 expression in the hippocampus of THY-Tau22 mice and wild-type littermates at the age of 12 months. Labelling of CCL3 (red) with the microglial marker Iba1 or the astrocyte marker GFAP (green) revealed clustered CCL3 staining solely in Iba1-positive cells (arrowheads and inset) in transgenic tau mice. To a lesser extent, such clusters are present in wild-type animals. Scale bar = 20 µm.

Mentions: To gain further insights into the relationships between tau pathology and neuroinflammation, we performed a microarray study on hippocampal mRNA samples from 12 month-old wild-type and THY-Tau22 mice (n = 7/group), to evaluate global gene expression changes associated with the development of tauopathy. As shown in Supplementary Table 2, 32 genes were identified as differentially expressed, with 28 genes being upregulated and only four genes downregulated in THY-Tau22 mice, as compared to wild-type animals. Most of the upregulated genes were associated with immune responses, in line with GO-Term Enrichment analysis (Supplementary Table 2). Expression changes of uncovered immune markers (indicated as bold in the Supplementary Table 2) were validated by quantitative PCR using independent mRNA samples. For most markers, such analysis demonstrated an age-dependent increased expression in tau transgenic mice as compared to wild-type littermates (Fig. 2A and Supplementary Fig. 2). Altogether, these data indicate that significant neuroinflammatory responses progressively develop along with tau pathology and memory deficits in the hippocampus of THY-Tau22 mice.Figure 2


Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy
Age-dependent upsurge of chemokines in the hippocampus of THY-Tau22 mice. (A) Quanititative PCR analysis of Ccl3, Ccl4, Ccl5 and Cxcl5 mRNAs revealed a significant and generally progressive overexpression in the hippocampus of transgenic animals as compared to wild-type (WT). Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 5–13/group. (B) ELISA determinations of hippocampal CCL3, CCL4 and CCL5 levels in wild-type and THY-Tau22 mice at all ages. The three chemokines were found significantly increased in tau animals, CCL3 being the earliest upregulated chemokine. Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–8/group. (C) Immunofluorescence analysis of CCL3 expression in the hippocampus of THY-Tau22 mice and wild-type littermates at the age of 12 months. Labelling of CCL3 (red) with the microglial marker Iba1 or the astrocyte marker GFAP (green) revealed clustered CCL3 staining solely in Iba1-positive cells (arrowheads and inset) in transgenic tau mice. To a lesser extent, such clusters are present in wild-type animals. Scale bar = 20 µm.
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aww270-F2: Age-dependent upsurge of chemokines in the hippocampus of THY-Tau22 mice. (A) Quanititative PCR analysis of Ccl3, Ccl4, Ccl5 and Cxcl5 mRNAs revealed a significant and generally progressive overexpression in the hippocampus of transgenic animals as compared to wild-type (WT). Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 5–13/group. (B) ELISA determinations of hippocampal CCL3, CCL4 and CCL5 levels in wild-type and THY-Tau22 mice at all ages. The three chemokines were found significantly increased in tau animals, CCL3 being the earliest upregulated chemokine. Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus wild-type (3 months) using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–8/group. (C) Immunofluorescence analysis of CCL3 expression in the hippocampus of THY-Tau22 mice and wild-type littermates at the age of 12 months. Labelling of CCL3 (red) with the microglial marker Iba1 or the astrocyte marker GFAP (green) revealed clustered CCL3 staining solely in Iba1-positive cells (arrowheads and inset) in transgenic tau mice. To a lesser extent, such clusters are present in wild-type animals. Scale bar = 20 µm.
Mentions: To gain further insights into the relationships between tau pathology and neuroinflammation, we performed a microarray study on hippocampal mRNA samples from 12 month-old wild-type and THY-Tau22 mice (n = 7/group), to evaluate global gene expression changes associated with the development of tauopathy. As shown in Supplementary Table 2, 32 genes were identified as differentially expressed, with 28 genes being upregulated and only four genes downregulated in THY-Tau22 mice, as compared to wild-type animals. Most of the upregulated genes were associated with immune responses, in line with GO-Term Enrichment analysis (Supplementary Table 2). Expression changes of uncovered immune markers (indicated as bold in the Supplementary Table 2) were validated by quantitative PCR using independent mRNA samples. For most markers, such analysis demonstrated an age-dependent increased expression in tau transgenic mice as compared to wild-type littermates (Fig. 2A and Supplementary Fig. 2). Altogether, these data indicate that significant neuroinflammatory responses progressively develop along with tau pathology and memory deficits in the hippocampus of THY-Tau22 mice.Figure 2

View Article: PubMed Central - PubMed

ABSTRACT

The role of immune responses in the cognitive impairments associated with tauopathy is unclear. Laurent et al. identify a CD8+ T-cell infiltration in the hippocampus of THY-Tau22 transgenic mice. T-cell depletion reverses spatial memory deficits in these animals, supporting a role for hippocampal T-cell infiltration in tau-driven cognitive impairments.

No MeSH data available.


Related in: MedlinePlus