B cell-immunoglobulin axis to explain aging onset of Alzheimer's Disease

National Institute On Aging

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Abstract

Aging is significant risk factor for dementia and Alzheimers disease (AD). Although aging also dysregulates immune cells, particularly B cells, their role in aging-associated neuro-inflammation remains unclear. By hypothesizing that B-cell function can change in aging, here we continue our study of the role of B cells in protection and promotion of neuro-degenerative diseases. While protection can be mediated by production of antibody and immunoregulatory cytokines, we recently reported that 4BL cells (pathogenic B1 B cells we found in elderly hosts, Lee-Chang et al., Blood, 2014; J. Immunol., 2016) can facilitate neuroinflammation/ degeneration. Although previous results from our group and others indicate to protective benefit of Abeta-specific antibody in hosts with AD, it remains unclear whether the same immunoglobulin is also causing neuroinflammation in the hosts aberantly expressing Abeta and thus forming plaques in the brain, such as in AD and Down Syndrome (DS). The benefit of our in house generated DNA vaccine (Olkhanud et al., Vaccine 2013) in mice with DS was reported last year. In collaboration with professor Okun (Bar-Ilan University, Israel), we showed that our vaccine can reduce Abeta-caused dementia in mice with DS upon direct or maternal immunization (Illouz et al., Vaccine, 2021). Because vaccine response in aged hosts is usually impaired, here we devised a novel strategy for inducing amyloid beta (Ab)-specific antibody responses in aged mice that model Alzheimers disease (AD) by first priming with a vaccine carrier when the mice were young. We hypothesized that priming would establish a memory response that could be boosted at older, immunosenescent age. We demonstrate that the deficit in the induction of humoral responses in 18 m-old WT C57BL/6J and 12 m-old 5xFAD mice, an early-onset AD (EOAD) model, was indeed reversed if the mice were primed with HBsAg alone and then boost-immunized at an older age with AbCoreS. Compared with unprimed AD mice, the prime in young and boost in old strategy resulted in more efficient control of AD-related neuropathology. The results of this study we recently published (Illouz et al., Vaccine, 2021; Communic. Biol, 2021). Immunofluorescent staining of brains of mice detected significant amounts of immunoglobuulins in the brain of AD mice. These immunoglobulins are mostly associated with Abeta plaques. Importantly, depletion of circulating B cells with anti-CD20/B220 antibody markedly decreases brain immunoglobulins (Its) as well reverses AD symptomes in mice with AD. Thus, we think that the brain Igs are facilitating AD via exacerbation of brain inflammation in AD. To test these possibility, we have created AD mcei that are deficient in immunoglobulins, such as IgA or cannot generate switched Igs (AID KO). In addition, we initiated attemts to enhance Abeta antibody in mice with AD. For this purpose, i.e. to enhance the generation of Abeta-specific antibody, we "converted" our DNA vaccine to RNA vaccine, a most superior strategy. The RNA vaccine was tested in 5xFAD mice at the onset of AD symptoms. Although the RNA-based vaccine generated significantly higher amounts of Abeta-specific antibody as compared to protein or DNA-based vaccine expressing the same antigen, surprisingly we failed to reverse AD symptoms. Preliminary data suggest that the vaccine may instead exacerbate the disease symptoms. To confirm and understand this unexpected result, we are repeating the experiment in a larger cohort of mice. In addition, we are reapeating the study in younger and older cohorts of 5xFAD mice. These results are in concordance with our recent finding that genetic B-cell deficiency (B-KO) blocks manifestation of AD symptoms in all three widely used transgenic AD mouse models, such as 3xTgAD, APP/PS1 and 5xFAD mice (respectively termed 3xTgAD/BKO, 2xTgAD/BKO and 5xFAD/BKO). The B-KO almost completely reversed the AD symptoms despite expression of AD-promoting transgenes. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO, 5xFAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. 2xTgAD/BKO, 5xFAD/BKO and 3xTgAD/BKO mice contained significantly fewer A-beta plaques in the brain subiculum than their age- and sex-matched littermates. Since we found that B cells were increased in hippocampus of AD mice, we proposed that they exacerbate disease-associated microglia (DAG) by producing immunoglobulins and possibly proinflammatory factors in the brain. This presumably explains why B-KO markedly reduces both immunoglobulin and DAG in the brain. BKO reverses decreased presence of TGFb-expressing homeostatic microglia, further implying the importance of B cells in promoting AD pathology. Clinical implication of our finding is that inactivation or depletion of B cells may have therapeutic benefit. Indeed, we showed that antibody-mediated transient depletion of B cells at the onset of AD manifestation in 3xTgAD and 5xFAD mice can significantly reverse AD symptoms. This study was recently published (Ki et al., Nature Commun. 2021). Overall, the study is progressing as planned.