Pulmonary B Lymphocytes Ameliorate Alzheimer's Disease-Like Neuropathology

Abstract Increasing evidences reveal that the peripheral immune system is involved in the pathogenesis of Alzheimer's disease (AD). Here, we report that pulmonary B lymphocytes mitigate beta-Amyloid (Aβ) pathology in 5xFAD mice. The proportion of B cells, rather than T cells, increases within the brain, meningeal and lung tissues in 3-month-old 5xFAD mice. Deletion of mature B cells aggravates Aβ load and memory deficits of 5xFAD mice. Mechanistically, pulmonary B cells can migrate to the brain parenchyma and produce interleukin-35, which inhibits neuronal β-site APP-cleaving enzyme 1 expression, and subsequently reduces the production of Aβ. In turn, pulmonary B cell proliferation is associated with activation of the toll-like receptor/nuclear factor kappa-B pathway through elevated Aβ that is drained from the brain parenchyma to the lungs via meningeal lymphatics. Furthermore, promoting pulmonary B cell proliferation via overexpression of B-cell-activating factor ameliorates brain Aβ load and improves cognitive functions of 10-month-old 5xFAD mice. Together, these results highlight the lungs as both immune targets and effector organs in Aβ pathogenesis. Pulmonary B cells could serve as a potential target against AD.