Blood-derived amyloid-[beta] protein induces Alzheimer's disease pathologies

The amyloid-[beta] protein (A[beta]) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that A[beta] deposited in the brain originates from the brain tissue itself. However, A[beta] is generated in both brain and peripheral tissues. Whether circulating A[beta] contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human A[beta] originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and A[beta] plaques after a 12-month period of parabiosis. AD-type pathologies related to the A[beta] accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived A[beta] can enter the brain, form the A[beta]-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting A[beta] metabolism in both the brain and the periphery.