The adaptive immune cells also play important role in proper function of the central neural system (CNS). However, their role in Alzheimer's disease (AD) remains poorly understood despite the fact that a risk for dementia and AD increases together with the dysregulation of immune cells in the elderly. Although our previous results suggest that that B cells can alleviate AD symptoms via generation of Ab plaque-neutralizing antibody (Olkhanud et al, Vaccine, 2011), we also found that B cells acquire pathogenic functions in aging. Since these results for the first time indicate that B cells may also promote AD, we have initiated a new study to test the role of aging B cells in AD. For this purpose we used 2 types of mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice, respectively. The mice were crossed with B-cell deficient (BKO) mice to generate 2xTgAD/BKO and 3xTgAD/BKO mice. Our results reveal that the loss of B cells in 2xTg-AD mice is lethal, as they die by 2-3 month of age, suggesting the protective/beneficial role of B cells. However, the loss of B cells in in 3xTgAD/BKO mice appears to alleviate AD, thus indicating that B cells can also be pathogenic and promote AD in aging. Compared to age/sex-matched B-cell sufficient littermates, 3xTgAD/BKO mice exhibit less anxiety and improved memory deficits (not depicted). Despite high levels of APP production in neurons, 3xTgAD/BKO mice contain significantly fewer Ab-plaques in the brain subiculum than age-matched 3xTg-AD mice (not depicted). The over activated microglia in 3xTgAD mice, another hallmark of AD pathology, is markedly reduced in age/sex-matched 3xTgAD/BKO mice. Moreover, IFN-expressing CD8+T cells significantly enriched in 3xTgAD mice are markedly reduced in B-cell deficient 3xTgAD/BKO mice. We also confirmed this results by transiently depleting B cells.Transient depletion of B cells in 3xTgAD mice or genetic B-cell deficiency (3xTgAD/BKO mice) ameliorates AD. The loss of B cells markedly reverses the reduced expression of immunoregulatory factors (IL-10 and TGF) and increased expression of IL1 in MG in of 3xTgAD mice. However, we find that B cells by themselves do not infiltrate the hippocampus or frontal cortex of AD mice, suggesting that their involvement is indirect and possibly via activating other immune cells. Considering the superb ability of 4BL cells to induce antigen-specific cytolytic CD8+T cells, we think that B cells activate CD8+T cells that subsequently infiltrate hippocampus and frontal cortex and thereby promote AD. We find significant infiltration of CD8+T cells in those areas of AD mouse brain. Moreover, we think that by producing IFN, CD8+T cells can then control brain Trp metabolism increasing Kyn/Trp ratio and thus affecting production of neurotoxic factors, serotonin and NAD+. Overall, the study is progressing as planned. By experimenting with 3xTgAD mice, which develop AD pathology when pathogenic B cells/4BL cells become enriched in old age, for the first time we link aging B cells to onset of the disease. Collectively, our preliminary results indicate that B cells appear to facilitate aging-associated onset of AD by targeting inflammatory immune cells and affecting Trp pathway. To complete this unique study, we are planning to repeat the experiment with a larger number of mice and with a longer time of B-cell depletion. We will also evaluate Trp metabolites and Kyn/Trp ratio in 3xTgAD/BKO mice that are mock treated or replenished with old and young mouse B cells.
| Eitan, Erez; Green, Jamal; Bodogai, Monica et al. (2017) Age-Related Changes in Plasma Extracellular Vesicle Characteristics and Internalization by Leukocytes. Sci Rep 7:1342 |
| Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny (2017) Potential importance of B cells in aging and aging-associated neurodegenerative diseases. Semin Immunopathol 39:283-294 |
