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. 2018 Aug 16;10(1):81.
doi: 10.1186/s13195-018-0412-9.

IgM response against amyloid-beta in aging: a potential peripheral protective mechanism

Sudhanshu Agrawal  1 , Edsel M Abud  2 , Shikha Snigdha  2 , Anshu Agrawal  3
Affiliations

IgM response against amyloid-beta in aging: a potential peripheral protective mechanism

Sudhanshu Agrawal et al. Alzheimers Res Ther. .

Abstract

Background: The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (Aβ) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of Aβ.

Methods: We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to Aβ peptide 1-42, Aβ fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD.

Results: Our studies revealed that DCs from healthy aged subjects display weak reactivity towards the Aβ peptide and no reactivity towards Aβ fibrils and tau compared with their young counterparts. An analysis of old and young PBMCs revealed that there is no significant T-cell memory against Aβ peptide, fibrils, or tau. Remarkably, the plasma levels of IgM antibodies specific to Aβ peptide 1-42 were significantly increased in aged subjects compared with young subjects, while IgG levels were comparable. Aβ peptide-specific IgM and IgG levels were also determined in the plasma of AD subjects compared with age-matched controls to demonstrate that the immune response against Aβ is stronger in AD patients. A decline in Aβ peptide-specific IgM antibodies was observed in AD patients compared with age-matched controls. In contrast, the levels of IgG as well as interleukin-21, the major cytokine involved in class switching, were increased in AD and patients with mild cognitive impairment, indicating a strong immune response against Aβ.

Conclusions: Collectively, low immunogenicity of Aβ in healthy controls may prevent inflammation while the generation of specific IgM antibodies may help in the clearance of Aβ in healthy subjects.

Keywords: Amyloid beta; Dendritic cells; Human; IgM antibody.

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Conflict of interest statement

Consent for publication

The study was approved by the Institutional Review Board of the University of California, Irvine (UCI). Informed consent was obtained from the subjects.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Dendritic cells (DCs) from aged subjects display increased secretion of inflammatory chemokines and cytokines in response to amyloid-beta (Aβ) peptide. DCs from healthy aged and young subjects were cultured overnight with Aβ42 peptide (pep), Aβ fibril (fib), and tau protein at 10 μg/ml. Cytokine secretion in the supernatants was quantified by ELISA. Bar graphs depict the levels of a chemokines (C-X-C motif chemokine 10 (CXCL-10), C-C motif chemokine ligand (CCL)-4, and CCL-2) and b cytokines (interleukin (IL)-6 and IL-1β). Results are shown as mean ± SEM of 18 different aged and 18 different young subjects. p values are based on two-tailed, parametric paired t tests with 95% confidence interval. Comparison of stimulated DCs in each group was performed against the control of the same age group
Fig. 2
Fig. 2
Amyloid-beta (Aβ) activates dendritic cells (DCs) from aged subjects which prime CD4 T cells to secrete tumor necrosis factor (TNF)-α. Aβ42 peptide (pep)-, Aβ fibril (fib)-, and tau protein-exposed DCs from aged and young subjects were cultured with purified CD4 T cells for 6 days. Bar graphs depict the level of the cytokines TNF-α, interferon (IFN)-γ, interleukin (IL)-17, and IL-10 in the supernatants after 6 days as determined by specific ELISA. Results are shown as mean ± SEM of 14 different aged and 14 different young subjects. p values are based on two-tailed, parametric paired t tests with 95% confidence interval. Comparison of stimulated DCs in each group was performed against the control of the same age group
Fig. 3
Fig. 3
Amyloid-beta (Aβ) peptide does not induce T cell cytokine secretion from peripheral blood mononuclear cells (PBMCs) of aged and young subjects. PBMCs from aged and young subjects were stimulated with Aβ42 peptide (pep) for 6 days. Bar graphs depict the level of the cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-17, and IL-10 in the supernatants after 6 days as determined by specific ELISA. Results are shown as mean ± SEM of 6 different aged and 6 different young subjects. p values are based on two-tailed, parametric paired t tests with 95% confidence interval. Comparison of stimulated DCs in each group was performed against the control of the same age group. fib fibril
Fig. 4
Fig. 4
Amyloid-beta (Aβ)42 peptide-specific antibodies of IgM isotype are increased in aged subjects. The levels of Aβ42-specific antibodies as well as Aβ scrambled peptide were measured from the plasma samples of aged and young subjects using an in-house ELISA. a Dot plots depict the ratio of Aβ-specific IgG and IgM antibodies to scrambled peptide antibodies. Results are shown as mean ± SD of 43 different aged and 43 different young subjects. b Dot plots depict the ratio of Aβ42-specific IgG and IgM antibodies to scrambled peptide antibodies in male and female aged and young subjects. Results are shown as mean ± SD of 9 aged males and 20 young males and 34 aged females and 23 young females. p values are based on two-tailed, unpaired t tests with 95% confidence interval. O.D. optical density
Fig. 5
Fig. 5
Amyloid-beta (Aβ)42 peptide-specific antibodies of IgM isotype are decreased in Alzheimer’s disease (AD) patients compared with healthy controls (HC). The levels of Aβ42-specific antibodies as well as Aβ scrambled peptide were measured from the plasma samples of AD patients, those with mild cognitive impairment (MCI), and age-matched healthy controls. a Dot plots depict the ratio of Aβ42-specific IgG and IgM antibodies to scrambled peptide antibodies. b Dot plot depicts the levels of IL-21 in the same samples. Results are shown as mean ± SD of 26 AD patients, 26 MCI patients, and 26 healthy controls. p values are based on one0way ANOVA followed by Tukey’s test with two tails and 95% confidence interval
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