The role of immune cells in Alzheimer's disease

National Institute On Aging

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Abstract

The role of B cells in Alzheimer's disease (AD) remains poorly understood even though we and others showed their benefit as producers of antibody that help to eliminate neurotoxic beta-amyloid depositions (Ab plaques) (Olkhanud et al, Vaccine, 2011). However, besides this potential benefit of B cells, the role of B cells in AD pathology remains unknown. Because the onset of sporadic AD coincides with the dysregulation of B cells in aging, we hypothesized that B cells could be promoting AD. Since B cells are thought not to be involved nor infiltrate the brains in AD, to test our hypothesis we evaluated B cells in 3 different but widely used mouse models of AD, such as 3xTgAD, APP/PS1 and 5xFAD mice. We also generated B-cell deficient (BKO) mice that develop AD in young (2xTgAD and 5xFAD mice) and old age (3xTgAD mice) by crossing BKO mice with 2xTgAD, 5FAD and 3xTgAD mice, respectively. As we expected, the loss of B cells in these mice 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 Ab-plaques in the brain subiculum than their age- and sex-matched littermates. Mechanistically, we found that B cells infiltrate brain parenchyma and produce potentially inflammatory immunoglobulins that presumably exacerbate disease-associated microglia. As such, mice B-cell deficient AD mice markedly decreased brain B cells and immunoglobulins, and disease-associated microglia and increased TGFb-expressing homeostatic microglia. Thus, contrary to current assumption, for the first time we linked AD onset to B cells, indicating that inactivation or depletion of B cells may have therapeutic benefit. Indeed, we showed that antibody-mediated transient depletion of B cells from the circulation of mice with AD, such as 3xTgAD, APP/PS1 and 5xFAD mice can significantly reverse AD symptoms. Importantly, we detected significant therapeutic benefit even when B cells were depleted at the onset of AD. Overall, for the first time we demonstrate that B cells play pathogenic role in AD and their transient depletion from the circulation can delay AD onset. Despite significant problems with the COVID-19 quarantine-associated loss of essential mouse strains and time, we have successfully completed this study. This study has been recently published (Ki et al., Nature Commun. 2021).