Bacille Calmette-Guérin Attenuates Vascular Amyloid Pathology and Maximizes Synaptic Preservation in APP/PS1 Mice Following Active Amyloid-β Immunotherapy

Abstract Despite effective clearance of parenchymal amyloid-β (Aβ) in Alzheimer’s disease (AD) patients, Aβ immunotherapy accelerates the accumulation of vascular Aβ (VAβ) in the brain and is associated with numerous complications. We have previously shown that bacille Calmette-Guerin (BCG) immunization facilitates protective immunity and promotes monocyte recruitment to the brain of APP/PS1 mice. Here, we confirmed that the Aβ vaccine (4Aβ1-15) exacerbates leptomeningeal VAβ deposits in this mouse model, which coincides with a decrease in the number of cerebrovascular endothelial cells (CD31+) and pericytes (CD13+), infiltration of neutrophils into the brain, and induction of cerebral microhemorrhage. Moreover, immune stimulation by BCG abrogates the development of the VAβ-associated pathology observed in 4Aβ1-15-treated mice. Consistent with the results of our previous study, BCG treatment is required for the upregulation of anti-inflammatory cytokine interleukin (IL)-10 in the brain. The data of flow cytometry-based in vivo assays indicated that BCG treatment selectively enhances Aβ phagocytosis by recruited macrophages (CD11b+CD45high) and that Aβ phagocytosis by microglia (CD11b+CD45int) is decreased. Furthermore, combined 4Aβ1-15/BCG treatment is more effective than 4Aβ1-15 monotherapy in synaptic preservation, and this combined treatment enhances the learning efficiency of mice in the Morris water maze test. Overall, our study indicates that BCG treatment results in better vascular Aβ clearance and synaptic preservation in APP/PS1 mice after 4Aβ1-15 immunotherapy suggesting that the combination of Aβ-targeted therapy with an immunomodulatory strategy may improve the efficacy of the Aβ peptide vaccine in AD.