Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-beta isoform(s) (predominantly amyloid-beta(40)) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-beta(40) selective antibody, to attenuate amyloid-beta accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-beta accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-beta biochemically. We hypothesized that the reduction in vascular amyloid-beta(40) after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-beta(40) in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-beta(40) levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-beta species that may otherwise be detrimental to normal vessel function.