| First Author | Xiong M | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 581 | PubMed ID | 33597265 |
| Mgi Jnum | J:304463 | Mgi Id | MGI:6508651 |
| Doi | 10.1126/scitranslmed.abd7522 | Citation | Xiong M, et al. (2021) APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med 13(581) |
| abstractText | The epsilon4 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-beta (Abeta) 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 Abeta 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-Abeta 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 Abeta antibody that removes parenchymal Abeta but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Abeta deposition including CAA compared to a control antibody, whereas the anti-Abeta antibody had no effect on CAA. Furthermore, the anti-Abeta 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. |
