ALZHEIMERS RESEARCH PROJECT: B cells promote Alzheimers disease via cytolytic CD8+ T cells

National Institute On Aging

Investigators

Abstract

According to the prevailing Amyloid cascade hypothesis, Alzheimers disease (AD) is caused by decades-long deposition of neurotoxic amyloid Ab-peptide aggregates (Ab plaques) in the brain. It leads to a chain of pathological events, including tauopathy, astrogliosis, accumulation of disease associated microglia (DAM), synaptic and neuronal dysfunction, and eventually dementia. However, the role of adaptive immunity remains unclear. Here we continue our recent discovery that the AD manifestation also depends on B cells. Contrary to the assumption that the adaptive immunity plays a negligible role in AD, we reported that the disease cannot progress if B cells are lost in 3 distinct mice with early onset of AD (EOAD) (Kim et al., Nature Comm, 2021). However, the mechanism how B cells promote AD-like pathology remains unknown. In the present work, we aimed to understand the increased presence of CD8+ T cells in the brain of humans and transgenic mice with AD. Since B cells in AD mice upregulate MHC-I molecules as well as co-stimulatory molecules, we hypothesized that B cells are responsible for the induction of CD8+ T cells that increase in the brain of 5xFAD mice. In the brain parenchyma of 5xFAD mice as well as humans with AD, we find CD8+ T cells are tightly complexed with microglia around Abeta plaques, implying that CD8+ T cells probably affect AD pathology by controlling function of microglia. To test this possibility, we performed ex vivo co-culture experiments of CD8+ T cells with primary microglia. Our preliminary results indicate that CD8+ T cells from the brain of AD, but not non-AD, mice impair microglial phagocytosis. At present, we are testing this possibility to elucidate the mechanism by which CD8+ T cells control microglia. Phenotypically, the brain CD8+ T cells resemble DP8 cells, the CD39+ and CD73+ CD8+ T cells we recently discovered in aged hosts, expressing exhaustion and tissue resident memory markers. In-depth characterization of these CD8+ T cells in the brain of 5xFAD mice indicate that they also express CXCR6, suggesting that they probably are recruited to activated microglia secreting CXCL16. At present, we are testing this possibility and to link CXCR6/CXCL16 axis to the formation of CD8+ T cell-microglia complexes. Notably, genetic or antibody-mediated B cell ablation almost completely eliminates increase of exhausted DP8-like cells and their complexes with microglia in the brain of 5xFAD mice as well as AD-like pathology, suggesting that B cells could indeed be responsible for the induction of brain-infiltrating but pathogenic CD8+ T cells. Mechanistically, we think that upon peripheral activation with a brain antigen (such as Abeta peptide)-presenting B cells, CD8+ T cells infiltrate the brain and then bind to microglial cells affecting their activity. As such, the immunization of 5xFAD mice with Abeta-encoding RNA vaccine not only increases CD8+ T cells in the brain, but also exacerbates AD-like pathology. Conversely, antibody-mediated depletion of CD8+ T cells in the circulation reduces brain CD8+ T cells and AD-like pathology.Overall, our findings, which we recently published in BBI (Xin et al., 2024), underscore overlooked importance of the adaptive immunity in AD. It reveals that the pathogenic importance of B cells in neurodegeneration and and AD. The B-cell-to-CD8 cell crosstalk promotes AD-like pathology and neurodegeneration through activation of microglia in the brain. Moreover, we also found that B cells exacerbate neurodegeneration through the generation of ectopic lymphoid structures (ELS) in the meninges of aged mice and mice with AD in an age- and sex-dependent manner. This finding we recently published in PNAS (Davidi et al., 2025).