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. 2019 Sep;176(18):3544-3557.
doi: 10.1111/bph.14586. Epub 2019 Mar 3.

Neutralization of IL-17 rescues amyloid-β-induced neuroinflammation and memory impairment

Claudia Cristiano  1 , Floriana Volpicelli  1   2 , Pellegrino Lippiello  1 , Benedetta Buono  1 , Federica Raucci  1 , Marialuisa Piccolo  1 , Asif Jilani Iqbal  3 , Carlo Irace  1 , Maria Concetta Miniaci  1 , Carla Perrone Capano  1   2 , Antonio Calignano  1 , Nicola Mascolo  1 , Francesco Maione  1
Affiliations

Neutralization of IL-17 rescues amyloid-β-induced neuroinflammation and memory impairment

Claudia Cristiano et al. Br J Pharmacol. 2019 Sep.

Abstract

Background and purpose: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD-related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL-17 has not been well addressed. Herein, we investigate the effects of IL-17 neutralizing antibody (IL-17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid-β (Aβ)-induced neuroinflammation and memory impairment in mice.

Experimental approach: Aβ1-42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL-17Ab via i.c.v. either at 1 h prior to Aβ1-42 injection or IN 5 and 12 days after Aβ1-42 injection. After 7 and 14 days of Aβ1-42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas.

Key results: Pretreatment with IL-17Ab, given, i.c.v., markedly reduced Aβ1-42 -induced neurodegeneration, improved memory function, and prevented the increase of pro-inflammatory mediators in a dose-dependent manner at 7 and 14 days. Similarly, the double IN administration of IL-17Ab after Aβ1-42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines.

Conclusion and implications: These findings suggest that the IL-17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL-17Ab IN administration in reducing Aβ1-42 neurodegeneration points to a possible future therapeutic approach in patients with AD.

Linked articles: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Experimental flow chart for the in vivo model, behavioural studies, and biochemical and molecular analysis with acute and subchronic treatment with IL‐17Ab
Figure 2
Figure 2
Effect of IL‐17Ab i.c.v. and IN‐treated mice on olfactory discrimination at 7 (a) and 14 (b) days and on novel object recognition at 7 (c) and 14 (d) days. Data were expressed as mean ± SEM (n = 6 per group). # P ≤ 0.05, significantly different from Control‐treated group (Ctrl); *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Dunnett's post hoc test
Figure 3
Figure 3
Escape latency (a) and average speed (b) during training phase in the MWM test. Time spent in the target quadrant of the probe test at 7 (c) and 14 (d) days. (e) Schematic plots of probe test at 7 and 14 days for all experimental groups. Data were expressed as mean ± SEM (n = 6 per group). # P ≤ 0.05, significantly different from Control‐treated group (Ctrl); *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Bonferroni's post hoc test
Figure 4
Figure 4
Percent of correct alternations (a–c) and total arm entries (b–d) in the Y‐maze test. Data were expressed as mean ± SEM (n = 6 per group). # P ≤ 0.05, significantly different from Control‐treated group (Ctrl); *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Bonferroni's post hoc test
Figure 5
Figure 5
Effect of IL‐17Ab on the production of (a) Aβ1–42 (detected by ELISA assay and expressed as μg·ml−1), release of (b) S100B protein (detected by ELISA assay and expressed as μg·ml−1), and (c) MPO activity (detected by enzymic assay and expressed as mg per tissue) in total brain homogenates. Data were expressed as mean ± SEM (n = 6 per group). # P ≤ 0.05, significantly different from Control‐treated group (Ctrl); *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Dunnett's post hoc test
Figure 6
Figure 6
Representative immunofluorescence staining for GFAP and Iba‐1 in the hippocampus of (a–g) Ctrl, (b–h) IL‐17Ab i.c.v., (c–i) IL‐17Ab IN, (d–j) Aβ1–42, (e–k) Aβ1–42 + IL‐17Ab i.c.v., or (f–l) IL‐17Ab IN‐treated mice (scale bar 100 μm). Quantitative analysis of (m) GFAP and (n) Iba‐1 positive cells. Values are expressed as percent mean (±SEM) of positive cells of n = 6 mice in the hippocampus of Ctrl mice. # P ≤ 0.05, significantly different from Ctrl group; *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Bonferroni's post hoc test
Figure 7
Figure 7
Inflammatory fluids obtained from total brain homogenates of (b) Ctrl, (c) IL‐17Ab i.c.v., (d) IL‐17Ab IN, (e) Aβ1–42, (f) Aβ1–42 + IL‐17Ab i.c.v., or (g) IL‐17Ab IN‐treated mice were assessed using (a) a proteome profiler cytokine array panel; the modulated cytokines are shown in red. Mean changes (±SEM) of positive spots of three separate experiments with n = 6 mice were expressed as INT per mm2 of densitometric values (h–j). # P ≤ 0.05, significantly different from Ctrl group; *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Dunnett's post hoc test
Figure 8
Figure 8
Inflammatory fluids obtained from (a–g) hippocampus and (h–n) prefrontal cortex homogenates of (b and i) Ctrl, (c and j) IL‐17Ab i.c.v., (d and k) IL‐17Ab IN, (e and l) Aβ1–42, (f and m) Aβ1–42 + IL‐17Ab i.c.v., or (g and n) IL‐17Ab IN‐treated mice were assessed using (a and h) a proteome profiler cytokine array; the modulated cytokines are shown in red. Mean changes (±SEM) of positive spots of three separate experiments with n = 6 mice were expressed as INT per mm2 of densitometric values for both hippocampus (o) and prefrontal cortex (p). # P ≤ 0.05, significantly different from Ctrl group; *P ≤ 0.05, significantly different from Aβ1–42 peptide‐treated group; one‐way ANOVA with Dunnett's post hoc test
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