Manifestation of Alzheimer's Disease requires B cells

National Institute On Aging

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Abstract

The role of aging-linked immune dysregulation in dementia and Alzheimers disease (AD) remains poorly understood. Recently we proposed that AD requires B cells. We demonstrated that AD cannot progress if B cells are lost (Kim et al., Nature Commun., 2021). Thus, in addition to the benefit (as producers of antibody that reduces amyloid burden), B cells can also be pathogenic in AD. Our preliminary results indicate that the AD B cells resemble 4BL cells, potentially pathogenic B1 B cells, activated B cells we discovered in elderly hosts (Lee-Chang et al., Blood, 2014; J. Immunol., 2016). They promote insulin resistance in aging (Bodogai et al., Science Translational. Med, 2018). Although our previous results demonstrated importance of Abeta-specific antibody in protection from cognitive impairments caused by amyloid burden in AD and Down syndrome (DS) (Olkhanud et al., Vaccine 2013; Illouz et al., Vaccine, 2021; Illouz et al., Vaccine, 2021; Communic. Biol, 2021), our recent results suggest that the immunoglobulin (or even beta-specific antibody) may also participate in the AD manifestation. We evaluated immunoglobulin (Ig) in the brain of mice with AD using immunofluorescent staining. Compared with age/sex-matched mice, brain of AD mice was significantly increased in Ig. This Ig was mostly associated with Abeta plaques and microglia. Importantly, depletion of circulating B cells with anti-CD20/B220 antibody markedly decreased Ig in the brain and reversed AD symptoms in mice with AD. Thus, corroborating our hypothesis that the brain Ig may also facilitate AD, presumably via exacerbating brain inflammation. Since effector function of Ig depends on its isotype, we are testing whether protection or manifestation of AD can be linked to a specific Ig isotype switch in B cells. We therefore have created AD mice that are deficient in immunoglobulins, such as IgA (5xFAD-IgAKO) or cannot generate switched Igs (5xFAD/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. Our preliminary results indicate that 5xFAD/AID-KO mice do not affect amyloid burden nor cognitive impairments, implying that AD progresses despite the loss of secreted Igs. We did not test 5xFAD/IgA-KO mice yet, as due to loss of our breeder pairs during the COVID19 pandemic, the strain had to be rederived. Overall, the project is progressing, and some results of the study have been included in our recent manuscript submitted for publication (Wang et al., 2023).