Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer's Disease: A Case Control Study

Abstract

The neuropathological hallmarks of Alzheimer's disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (T_h) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCI_AD, n = 14), with MCI unlikely due to AD (MCI_other, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3⁺CD8^-IL-17A⁺IFNγ^- Th17 cells, CD3⁺CD8^-IL-17A^-IFNγ⁺ Th1 cells, and CD4⁺CD127^lowCD25⁺ regulatory T cells (T_regs) were assessed by flow cytometry. In addition, the correlations of the proportions of T_h subsets to cerebrospinal fluid biomarkers were studied. CD3⁺CD8^-IL-17A⁺IFNγ^- Th17 cells were significantly increased in subjects with MCI_AD compared to age- and sex-matched subjects with MCI_other and controls (MCI_AD mean = 1.13, SD = 0.77; MCI_other mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4⁺CD127^lowCD25⁺ T_regs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (r_{Treg|totalTau} = 0.43, p = 0.021, n = 28; r_Treg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (r_{Treg|totalTau =} -0.51, p = 0.007, n = 26). The increase of circulating CD3⁺CD8^-IL-17A⁺IFNγ^- Th17 cells in the early stages of AD and the association of CD4⁺CD127^lowCD25⁺ T_regs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.

Keywords: Alzheimer’s disease; Tau; Th1; Th17; amyloid beta; mild cognitive impairment; regulatory T cell.

Figure 1

Percentages of CD3⁺CD8⁻IL-17⁺IFNγ⁻ Th17 cells (A), CD3⁺CD8⁻IL-17⁻IFNγ⁺ Th1 cells (B), and CD4⁺CD127^lowCD25⁺ T_regs (C) as assessed with flow cytometry from donor derived cryopreserved peripheral blood mononuclear cells were compared between controls, mild cognitive impairment (MCI)_other, MCI_AD, and Alzheimer’s disease (AD) dementia. Data are summarized as combined box- and scatter plots (p-values from post hoc tests are shown *p < 0.05, **p < 0.01).

Figure 2

Scatter plots showing the relationship between the cerebrospinal fluid level of total Tau protein [pg/ml; (A,B)], pTau181 [pg/ml; (C,D)], Aβ42/Aβ40 ratio (E,F), and the percentage of CD4⁺CD127^lowCD25⁺ T_regs (A,C,E) and CD3⁺CD8⁻IL-17⁺IFNγ⁻ Th17 cells (B,D,F) in donors with Alzheimer’s disease (AD, black squares) and controls (nonAD, gray dots). The associations in AD group, nonAD group and all subjects combined were investigated with Spearman’s correlation. (Scatter plots with the linear regression lines for AD and nonAD groups and their 95% confidence intervals are shown; non-significant = n.s., *p < 0.05, **p < 0.01, **p < 0.001; r: Spearman’s correlation coefficient; R²: coefficient of determination.)