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

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

Impact of T cell depletion on spatial memory and hippocampal tau pathology in THY-Tau22 mice. (A) Effect of anti-CD3 antibody treatment on spatial memory using Y-maze task. While wild-type (WT) mice, regardless of treatment, exhibited a preference for the new arm, compared to the familiar arm, THY-Tau22 treated with the isotypic control did not demonstrate preference for the new arm, showing defective spatial memory. By contrast, anti-CD3 treated THY-Tau22 mice demonstrated a preference for the new arm similarly to control animals. Results are expressed as means ± SEM. ***P < 0.001 Familiar/Other (O) versus New (N) arms using one-way ANOVA. n = 6–19/group. (B) Effect of T cell depletion on hippocampal markers of synaptic plasticity. Hippocampal Arc and 14-3-3 immunoreactivities were found significantly decreased in THY-Tau22 mice treated with isotypic control versus wild-type mice and return to control level in THY-Tau22 mice treated with the anti-CD3 antibody. *P < 0.05, versus wild-type isotype, #P < 0.05 and ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–4/group. Hippocampal density of CD8+ T cells in the different experimental groups. Density of CD8+ T cells was significantly increased at 9 months of age in THY-Tau22 mice treated with isotype and returned to control level in THY-Tau22 mice treated with anti-CD3 antibody. *P < 0.05 versus wild-type isotype, ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–10/group. (D) AT8 immunostaining indicate a similar immunoreactivity in THY-Tau22 mice regardless of treatment. n = 8/group. Scale bar = 500 µM. (E) Anti-CD3 treatment did not impact human tau expression, truncation (t-tau) and hyper-phosphorylation at several phospho-epitopes in THY-Tau22 mice. n = 6–8/group. Results are expressed as a percentage of THY-Tau22 mice injected with isotype ± SEM. (F) Effect of anti-CD3 treatment upon mRNA expression of neuroinflammatory markers in the hippocampus of THY-Tau22 mice. **P < 0.01, ***P < 0.001 versus wild-type isotype, #P < 0.05 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–9/group.
© Copyright Policy - cc-by-nc
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382942&req=5

aww270-F6: Impact of T cell depletion on spatial memory and hippocampal tau pathology in THY-Tau22 mice. (A) Effect of anti-CD3 antibody treatment on spatial memory using Y-maze task. While wild-type (WT) mice, regardless of treatment, exhibited a preference for the new arm, compared to the familiar arm, THY-Tau22 treated with the isotypic control did not demonstrate preference for the new arm, showing defective spatial memory. By contrast, anti-CD3 treated THY-Tau22 mice demonstrated a preference for the new arm similarly to control animals. Results are expressed as means ± SEM. ***P < 0.001 Familiar/Other (O) versus New (N) arms using one-way ANOVA. n = 6–19/group. (B) Effect of T cell depletion on hippocampal markers of synaptic plasticity. Hippocampal Arc and 14-3-3 immunoreactivities were found significantly decreased in THY-Tau22 mice treated with isotypic control versus wild-type mice and return to control level in THY-Tau22 mice treated with the anti-CD3 antibody. *P < 0.05, versus wild-type isotype, #P < 0.05 and ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–4/group. Hippocampal density of CD8+ T cells in the different experimental groups. Density of CD8+ T cells was significantly increased at 9 months of age in THY-Tau22 mice treated with isotype and returned to control level in THY-Tau22 mice treated with anti-CD3 antibody. *P < 0.05 versus wild-type isotype, ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–10/group. (D) AT8 immunostaining indicate a similar immunoreactivity in THY-Tau22 mice regardless of treatment. n = 8/group. Scale bar = 500 µM. (E) Anti-CD3 treatment did not impact human tau expression, truncation (t-tau) and hyper-phosphorylation at several phospho-epitopes in THY-Tau22 mice. n = 6–8/group. Results are expressed as a percentage of THY-Tau22 mice injected with isotype ± SEM. (F) Effect of anti-CD3 treatment upon mRNA expression of neuroinflammatory markers in the hippocampus of THY-Tau22 mice. **P < 0.01, ***P < 0.001 versus wild-type isotype, #P < 0.05 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–9/group.

Mentions: Treatment of wild-type littermates with either anti-CD3 or control isotype did not significantly impact spatial memory. Indeed, as shown in Fig. 6A, wild-type animals spent significantly more time in the novel arm as compared to the other one (P < 0.001 versus other arm for both groups; one-way ANOVA). Accordingly, percentage of time spent in the novel arm was significantly above chance (i.e. >50%) in both groups (wild-type + isotype: P = 0.01; wild-type + anti-CD3: P = 0.027). As expected (Belarbi et al., 2011; Laurent et al., 2016), THY-Tau22 mice injected with control isotype exhibited impaired spatial memory as demonstrated by the lack of preference for the novel arm (P = 0.69 when compared to 50% chance, and P = 0.61 versus the other arm; one-way ANOVA). In contrast, THY-Tau22 animals treated with anti-CD3 antibody behaved like wild-type animals, spending significantly more time in the novel arm than the other arm (P = 0.011 when compared to 50% chance, P < 0.0001 versus other arm; one-way ANOVA), indicative of improved spatial memory upon T cell depletion (Fig. 6A). Impaired memory has been associated with altered plasticity in tau transgenic mice (Burlot et al., 2015). We then investigated to what extent anti-CD3 treatment impacted on markers known to modulate synaptic plasticity. Specifically, we studied expression of Arc and 14-3-3 proteins, both known to regulate hippocampal-dependent memory (Qiao et al., 2014; Minatohara et al., 2016). As shown in Fig. 6B, hippocampal expression of Arc and 14-3-3 significantly decreased, respectively, by 42.9 ± 1.9% (P = 0.016) and 23.0 ± 0.9% (P = 0.014) in THY-Tau22 injected with isotype compared to wild-type mice treated with isotype. Whereas anti-CD3 antibody did not impact on Arc and 14-3-3 expressions in wild-type mice, their levels were significantly increased in THY-Tau22 mice treated with the antibody (Arc: +32.2 ± 6.7%, P = 0.025 versus THY-Tau22 + isotype; 14-3-3: 25.6 ± 7.6 %, P = 0.023 versus THY-Tau22 + isotype, one-way ANOVA; Fig. 6B). Strikingly, prevention of spatial memory deficits was associated with a significant reduction in the density of CD8+ cells in the hippocampus of T-cell-depleted THY-Tau22 mice, reaching similar levels than in control littermates (Fig. 6C).Figure 6


Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy
Impact of T cell depletion on spatial memory and hippocampal tau pathology in THY-Tau22 mice. (A) Effect of anti-CD3 antibody treatment on spatial memory using Y-maze task. While wild-type (WT) mice, regardless of treatment, exhibited a preference for the new arm, compared to the familiar arm, THY-Tau22 treated with the isotypic control did not demonstrate preference for the new arm, showing defective spatial memory. By contrast, anti-CD3 treated THY-Tau22 mice demonstrated a preference for the new arm similarly to control animals. Results are expressed as means ± SEM. ***P < 0.001 Familiar/Other (O) versus New (N) arms using one-way ANOVA. n = 6–19/group. (B) Effect of T cell depletion on hippocampal markers of synaptic plasticity. Hippocampal Arc and 14-3-3 immunoreactivities were found significantly decreased in THY-Tau22 mice treated with isotypic control versus wild-type mice and return to control level in THY-Tau22 mice treated with the anti-CD3 antibody. *P < 0.05, versus wild-type isotype, #P < 0.05 and ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–4/group. Hippocampal density of CD8+ T cells in the different experimental groups. Density of CD8+ T cells was significantly increased at 9 months of age in THY-Tau22 mice treated with isotype and returned to control level in THY-Tau22 mice treated with anti-CD3 antibody. *P < 0.05 versus wild-type isotype, ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–10/group. (D) AT8 immunostaining indicate a similar immunoreactivity in THY-Tau22 mice regardless of treatment. n = 8/group. Scale bar = 500 µM. (E) Anti-CD3 treatment did not impact human tau expression, truncation (t-tau) and hyper-phosphorylation at several phospho-epitopes in THY-Tau22 mice. n = 6–8/group. Results are expressed as a percentage of THY-Tau22 mice injected with isotype ± SEM. (F) Effect of anti-CD3 treatment upon mRNA expression of neuroinflammatory markers in the hippocampus of THY-Tau22 mice. **P < 0.01, ***P < 0.001 versus wild-type isotype, #P < 0.05 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–9/group.
© Copyright Policy - cc-by-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382942&req=5

aww270-F6: Impact of T cell depletion on spatial memory and hippocampal tau pathology in THY-Tau22 mice. (A) Effect of anti-CD3 antibody treatment on spatial memory using Y-maze task. While wild-type (WT) mice, regardless of treatment, exhibited a preference for the new arm, compared to the familiar arm, THY-Tau22 treated with the isotypic control did not demonstrate preference for the new arm, showing defective spatial memory. By contrast, anti-CD3 treated THY-Tau22 mice demonstrated a preference for the new arm similarly to control animals. Results are expressed as means ± SEM. ***P < 0.001 Familiar/Other (O) versus New (N) arms using one-way ANOVA. n = 6–19/group. (B) Effect of T cell depletion on hippocampal markers of synaptic plasticity. Hippocampal Arc and 14-3-3 immunoreactivities were found significantly decreased in THY-Tau22 mice treated with isotypic control versus wild-type mice and return to control level in THY-Tau22 mice treated with the anti-CD3 antibody. *P < 0.05, versus wild-type isotype, #P < 0.05 and ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–4/group. Hippocampal density of CD8+ T cells in the different experimental groups. Density of CD8+ T cells was significantly increased at 9 months of age in THY-Tau22 mice treated with isotype and returned to control level in THY-Tau22 mice treated with anti-CD3 antibody. *P < 0.05 versus wild-type isotype, ##P < 0.01 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 3–10/group. (D) AT8 immunostaining indicate a similar immunoreactivity in THY-Tau22 mice regardless of treatment. n = 8/group. Scale bar = 500 µM. (E) Anti-CD3 treatment did not impact human tau expression, truncation (t-tau) and hyper-phosphorylation at several phospho-epitopes in THY-Tau22 mice. n = 6–8/group. Results are expressed as a percentage of THY-Tau22 mice injected with isotype ± SEM. (F) Effect of anti-CD3 treatment upon mRNA expression of neuroinflammatory markers in the hippocampus of THY-Tau22 mice. **P < 0.01, ***P < 0.001 versus wild-type isotype, #P < 0.05 versus THY-Tau22 isotype group, using using one-way ANOVA followed by a post hoc Fisher’s LSD test. n = 6–9/group.
Mentions: Treatment of wild-type littermates with either anti-CD3 or control isotype did not significantly impact spatial memory. Indeed, as shown in Fig. 6A, wild-type animals spent significantly more time in the novel arm as compared to the other one (P < 0.001 versus other arm for both groups; one-way ANOVA). Accordingly, percentage of time spent in the novel arm was significantly above chance (i.e. >50%) in both groups (wild-type + isotype: P = 0.01; wild-type + anti-CD3: P = 0.027). As expected (Belarbi et al., 2011; Laurent et al., 2016), THY-Tau22 mice injected with control isotype exhibited impaired spatial memory as demonstrated by the lack of preference for the novel arm (P = 0.69 when compared to 50% chance, and P = 0.61 versus the other arm; one-way ANOVA). In contrast, THY-Tau22 animals treated with anti-CD3 antibody behaved like wild-type animals, spending significantly more time in the novel arm than the other arm (P = 0.011 when compared to 50% chance, P < 0.0001 versus other arm; one-way ANOVA), indicative of improved spatial memory upon T cell depletion (Fig. 6A). Impaired memory has been associated with altered plasticity in tau transgenic mice (Burlot et al., 2015). We then investigated to what extent anti-CD3 treatment impacted on markers known to modulate synaptic plasticity. Specifically, we studied expression of Arc and 14-3-3 proteins, both known to regulate hippocampal-dependent memory (Qiao et al., 2014; Minatohara et al., 2016). As shown in Fig. 6B, hippocampal expression of Arc and 14-3-3 significantly decreased, respectively, by 42.9 ± 1.9% (P = 0.016) and 23.0 ± 0.9% (P = 0.014) in THY-Tau22 injected with isotype compared to wild-type mice treated with isotype. Whereas anti-CD3 antibody did not impact on Arc and 14-3-3 expressions in wild-type mice, their levels were significantly increased in THY-Tau22 mice treated with the antibody (Arc: +32.2 ± 6.7%, P = 0.025 versus THY-Tau22 + isotype; 14-3-3: 25.6 ± 7.6 %, P = 0.023 versus THY-Tau22 + isotype, one-way ANOVA; Fig. 6B). Strikingly, prevention of spatial memory deficits was associated with a significant reduction in the density of CD8+ cells in the hippocampus of T-cell-depleted THY-Tau22 mice, reaching similar levels than in control littermates (Fig. 6C).Figure 6

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