Abstract
This study examines the link between peripheral immune changes in perpetuation of the Alzheimer’s disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology.
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Data Availability
All relevant raw datasets analyzed during the current study are freely available from the corresponding author on reasonable request.
Abbreviations
- AD:
-
Alzheimer’s disease
- MCI:
-
Mild Cognitive Impairment
- HC:
-
Healthy Controls
- Aβ:
-
Amyloid beta
- APC:
-
Antigen presenting cells
- Tfh:
-
T follicular helper cells
- ADRC:
-
Alzheimer’s disease research center
- FE:
-
Fear Extinction
- CS:
-
conditioned stimulus
- PMA:
-
phorbol 12-myristate 13-acetate
- WT:
-
Wild type control mice
- CSF:
-
cerebrospinal fluid
- NMSOD:
-
Neuromyelitis Optica Spectrum Disorders
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Acknowledgements
We are grateful to UCI-ADRC for providing the serum samples from AD, MCI patients and controls.
Funding
The project described was supported by AG045216, AG064709 to A.A. and the California Institute for Regenerative Medicine DISC1–10079 to J.E.B. The UCI-ADRC is funded by NIH/NIA Grant P50 AG16573. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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J.E.B. maintained the 5xFAD mouse colony and performed molecular analyses and analyzed data. M.A.A. performed mice behavior experiments, analyzed data and prepared Figs. L.A.A. performed mouse behavior experiments. C.M. helped with processing of mouse tissues for staining. S.A. performed the human serum experiments and flow cytometry of mice cells. A.A. designed the study, analyzed the data, prepared the figures and wrote the manuscript. All authors were involved in discussions and writing of manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of California Irvine Institutional Research Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Since deidentified human serum samples were obtained from ADRC, the research was considered non-human subjects by UCI-IRB. Informed consent from subjects was obtained by ADRC.
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All animal experimentation procedures were performed in accordance with the guidelines provided by NIH and approved by the University of California Irvine Institutional Animal Care and Use Committee.
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Supplementary figure 1
The number of dense core Aβ-plaques increase with age in 5xFAD mice. (A-C) Representative images of Thio-S staining for WT and AD mice qualitatively demonstrate early disease pathology as shown by the accumulation of plaques by 4 months of age in the basal lateral amygdala and increases at 8 months of age (BLA; 20 × confocal imaging). Dot blot of the quantitative analysis of plaque number demonstrate the advancing AD pathology reflected by gross increase in plaque number in the AD brain between 4 and 8 months of age. All data are presented as mean + SEM (n = 4 mice per group). P values are derived from Student’s t test. (PNG 662 kb)
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Baulch, J.E., Acharya, M.M., Agrawal, S. et al. Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology. J Neuroimmune Pharmacol 15, 852–862 (2020). https://doi.org/10.1007/s11481-020-09908-9
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DOI: https://doi.org/10.1007/s11481-020-09908-9