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). In the present work, we also demonstrate that manifestation of AD also requires accumulation of CD8+ T cells in the brain. We found that brain parenchyma of mice with EOAD and humans with AD and MCI is significantly increased in CD8+ T cells. By experimenting with 5xFAD and APP/PS1 mice, we provide evidence that their increase is mediated by B cells. We found that B cells preferentially increase unique type of CD8+ T cells in the brain, such as exhausted effector memory, tissue resident CD8+ T cells expressing IFNg and ectonucleotidases involved in adenosine generation, CD39 and CD73. Mechanistically, upon peripheral activation with Ab peptides, CD8+ T cells infiltrate the brain to to affect microglial activity, explaining the significant AD-associated increase of CD8+ T cells complexed with microglia in the brain of mice and humans. As such, transient depletion of CD8+ T cells is sufficient to block AD development in mice, suggesting that the crosstalk between CD8+ T and B cells could be an attractive target for the development of effective therapeutics and safer vaccines to combat this disease in humans. This project is recently submitted for publication (Xin et al., 2023).