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

Monica Xiong1,2, Hong Jiang1, Javier Remolina Serrano1, Ernesto R Gonzales1, Chao Wang1, Maud Gratuze1, Rosa Hoyle1, Nga Bien-Ly3, Adam P Silverman4, Patrick M Sullivan5, Ryan J Watts3, Jason D Ulrich1, Gregory J Zipfel6, David M Holtzman7

  1. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
  2. Division of Biology and Biomedical Sciences (DBBS), Washington University School of Medicine, St. Louis, MO 63110, USA.
  3. Denali Therapeutics, South San Francisco, CA 94080, USA.
  4. Codexis, Redwood City, CA 94063, USA.
  5. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
  6. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
  7. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. holtzman@wustl.edu.

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.

Presented By Monica Xiong | ORCID iD

NeuroscienceNicholas Liao2021-02 (Feb)