Blood cell-produced amyloid-beta induces cerebral Alzheimer-type pathologies and behavioral deficits

It is traditionally believed that cerebral amyloid-beta (A beta) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce A beta. The role of peripherally produced A beta in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced A beta to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human A beta in the blood, and caused AD phenotypes including A beta plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood A beta levels, and alleviated brain A beta burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced A beta plays a significant role in AD pathogenesis, and the elimination of peripheral production of A beta can decrease brain A beta deposition and represents a novel therapeutic approach for AD.