APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function.

Abstract

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4 +/+ (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.

• Authors: 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 581 (02 17 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33597265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Amyloid beta-Peptides
• Apolipoproteins E

Topics

• Alzheimer Disease (therapy)
• Amyloid beta-Peptides (metabolism)
• Animals
• Apolipoproteins E (metabolism)
• Brain (metabolism)
• Cerebral Amyloid Angiopathy (therapy)
• Immunotherapy
• Mice
• Plaque, Amyloid