Serpin A3 is Increased in Cerebral Amyloid Angiopathy and ARIA

Abstract

Vascular pathology is an important contributor to dementia, and astrocyte dysfunction is increasingly recognized as a key mediator of cerebrovascular injury. Serpin A3 is a well-known marker of reactive astrocytes, yet its role in vascular degeneration in cerebral amyloid angiopathy and Alzheimers disease remains poorly defined. We combined analyses of single-nucleus transcriptomic datasets with western blotting and quantitative two- and three-dimensional microscopy of human brain tissue to characterize Serpin A3 expression, distribution, cellular sources, and neuropathological correlates in the human brain. Serpin A3 protein abundance was increased in cases with cerebral amyloid angiopathy and Alzheimers disease compared to neurological controls, both by western blot and quantitative microscopy. The tissue distribution of Serpin A3 was heterogeneous and was predominantly within astrocytes associated with degenerating arterioles. Serpin A3 was also detected around parenchymal beta-amyloid plaques. In a postmortem case of active and severe lecanemab-associated amyloid-related imaging abnormalities, light sheet microscopy revealed prominent Serpin A3 immunoreactivity around inflamed, dilated vessels and microhemorrhages, with Serpin A3 levels higher than those found in the Cerebral Amyloid Angiopathy cases. These findings identify Serpin A3 as a marker of cerebrovascular injury and astrocyte-driven inflammatory responses in cerebral amyloid angiopathy.