Lung memory B cells ameliorate Alzheimer's disease-like pathology in 5×FAD mice through the CXCL12-CXCR4 axis

Although most AD-related pathological studies are limited to the brain, increasing evidence has demonstrated the contribution of peripheral immune cells to the pathogenesis of AD. We recently demonstrated that meningeal B cells inhibit β-amyloid (Aβ) production in the frontal cortex of young 5×FAD mice. In this study, we explored the precise origin of meningeal B cells. We observed that the AD-like pathology in 5×FAD mice was exacerbated when the germinal center in the lung lymph nodes was specifically destroyed via the intratracheal instillation of anti-CD40 antibodies, whereas it was alleviated via the intratracheal instillation of AAV-mBAFF to overexpress B-cell activating factor in the lungs. We demonstrated that Aβ was drained from the brain via meningeal lymphatics and eventually traveled to the lungs, where it activated B cells via the TLR4/NF-ĸB signaling pathway, whereas the CXCL12-CXCR4 axis regulated lung B-cell infiltration into the frontal cortex. We revealed that the increased number of B cells in the lungs of 5×FAD mice mainly included memory B (Bmem) cells. The supplementation of lung Bmem cells mitigated AD-like pathology in B-cell-deficient μMT^-/-/5×FAD mice, which was abolished by using a CXCR4 Antagonist. The suppression of CXCL12 expression in frontal microglia via AAV-siCXCL12 inhibited the infiltration of CXCR4⁺ Bmem cells and increased the Aβ burden in the frontal cortex of 5×FAD mice. Collectively, our results demonstrate an unexpected protective effect of lung Bmem cells on AD-like pathology.

Alzheimer’s disease; CXCL12-CXCR4; TLR4/NF-ĸB pathway; lung-brain axis; memory B cells.