B Cell Depletion Reverses Measures of Alzheimer's Progression in Mouse Models

In today's open access paper, researchers report results that suggest the contribution of B cells, a type of immune cell, to the progression of Alzheimer's disease is meaningful. Approaches to the selective destruction of the B cell complement in mice are fairly well developed, given that it is not harmful in the short term to live without B cells, and the B cell population regenerates quite rapidly when it is depleted. Applying such a method to clear B cells in Alzheimer's mouse models resulted in slowing of progression in the early stages and reversal in the later stages of the condition.

The mechanism of interest here is chronic inflammation in the brain, important to the progression of neurodegenerative conditions. Removing B cells from the picture in some way breaks some of the feedback loops involved in the growing levels of inflammation characteristic of aging and Alzheimer's disease. While the researchers speculate on the details, more work would have to be carried out to pin down exactly what is going on here. B cells are by no means as well studied in the context of Alzheimer's disease as are other types of immune cell, such as microglia.

One interesting point relates to the cells known as age-associated B cells. These age-associated B cells build up with age, as the name might suggest, and are known to be pathological. Trying to remove them has been the motivation for a number of studies of targeted B cell clearance, and removing them does indeed produce benefits in old animals. The researchers here believe that age-associated B cells are not involved in the B cell related contribution inflammation of Alzheimer's disease, however. It is some more general participation of B cells in the state of the aging brain.

Therapeutic B-cell depletion reverses progression of Alzheimer's disease

We provide counterintuitive evidence for a "dark" side of B cells - they exacerbate manifestation of Alzheimer's disease (AD)-like symptoms in addition to producing potentially beneficial amyloid-β plaque-reducing immunoglobulins and expressing AD-ameliorating cytokines. Although the exacerbation in Rag-deficient APP and 5×FAD mice is linked to the loss of protective B cells and T cells, our data revealed that the genetic loss of B cells alone or their transient depletion at the onset of AD improves the disease symptoms of three different mouse models.

Unlike a recent report that linked AD progression to the reduction of anti-inflammatory B1a cells in 5×FAD mice, the numbers of B1a and B1b cells in peripheral blood, spleen, and cervical lymph nodes were either unaffected (in 5×FAD mice even when followed for 4, 7, and 12 months) or upregulated (in 3×TgAD and APP/PS1 mice). However, regardless of their numbers, we recently reported that the function of B1a cells is not static and is rather controlled by the inflammatory milieu. In the aged hosts, B1a cells lose their anti-inflammatory activity and acquire pathogenic functions, such as becoming 4-1BBL+ B1a cells (termed 4BL cells) that induce cytolytic granzyme-B+ CD8+ T cells and promote insulin resistance. In concordance, B1 cells (as well B2 cells, in some models) in AD mice also appeared to acquire an inflamed phenotype, as they upregulated expression of cytokines. Although age-associated B cells also accumulate in aging, we did not detect their involvement in our three types of mice with AD.

Consistent with a recent RNA-seq report that revealed presence of mature B cells in the brains of AD mice, our data indicate that AD increases B cells in the brain, and their IgG in the cortex and hippocampus parenchyma, which was often colocalized with amyloid-β plaques and activated microglia. As in multiple sclerosis and cognitive dysfunction following stroke, B cells in the brain presumably produce immunoglobulins and proinflammatory factors exacerbating AD-promoting neuroinflammation. Our data also indicate that the loss of B cells, thus immunoglobulin G, in the brain significantly retards the development of AD. Although the mechanism of this process is a topic of a different study, we think that brain IgG (or its immune complex) alone or in concert with B-cell cytokines exacerbates neuroinflammation in AD.