APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function
Monica Xiong, Hong Jiang, Javier Remolina Serrano, Ernesto R. Gonzales, Chao Wang, Maud Gratuze, Rosa Hoyle, Nga Bien‐Ly, Adam P. Silverman, Patrick M. Sullivan, Ryan J. Watts, Jason D. Ulrich, Gregory J. Zipfel, David M. Holtzman
Abstract
(5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.