Intracisternal injection of beta-amyloid seeds promotes cerebral amyloid angiopathy

Beta amyloid (A beta) is a key component of parenchymal A beta plaques and vascular A beta fibrils, which lead to cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). Recent studies have revealed that A beta contained in the cerebrospinal fluid (CSF) can re-enter into brain through paravascular spaces. However, whether A beta in CSF may act as a constant source of pathogenic A beta in AD is still unclear. This study aimed to examine whether A beta pathology could be worsened when CSF A beta level was enhanced by intra-cisternal infusion of aged brain extract containing abundant A beta in TgCRND8 host mice. TgCRND8 mouse is an AD animal model which develops predominant parenchymal A beta plaques in the brain at as early as 3 months of age. Here, we showed that single intracisternal injection of A beta seeds into TgCRND8 mice before the presence of A beta pathology induced robust prion-like propagation of CAA within 90 days. The induced CAA is mainly distributed in the cerebral cortex, hippocampus and thalamus of TgCRND8 mice. Surprisingly, despite the robust increase in CAA levels, the TgCRND8 mice had a marked decrease in parenchymal A beta plaques and the plaques related neuroinflammation in the brains compared with the control mice. These results amply indicate that A beta in CSF may act as a source of A beta contributing to the growth of vascular A beta deposits in CAA. Our findings provide experimental evidence to unravel the mechanisms of CAA formation and the potential of targeting CSF A beta for CAA.