TY - JOUR
T1 - APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function
AU - Xiong, Monica
AU - Jiang, Hong
AU - Serrano, Javier Remolina
AU - Gonzales, Ernesto R.
AU - Wang, Chao
AU - Gratuze, Maud
AU - Hoyle, Rosa
AU - Bien-Ly, Nga
AU - Silverman, Adam P.
AU - Sullivan, Patrick M.
AU - Watts, Ryan J.
AU - Ulrich, Jason D.
AU - Zipfel, Gregory J.
AU - Holtzman, David M.
N1 - Funding Information:
This work was supported by National Institute on Aging AG062027 (M.X.), NIH 5T32GM008151 (M.X.), NIH AG047644 (D.M.H.), the JPB Foundation (D.M.H.), NIH RF1 NS103276 (G.J.Z.), and 2P30AG019610 (E. Reiman and T. Beach). Images scanned on a NanoZoomer digital pathology system is courtesy of the Hope Center Alafi Neuroimaging Laboratory. WUCCI received support from Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD021629, for the purchasing of the Nikon A1R+ confocal microscope for capturing fluorescent staining.
Publisher 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
PY - 2021/2/17
Y1 - 2021/2/17
N2 - 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 Aβantibody 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.
AB - 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 Aβantibody 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.
UR - http://www.scopus.com/inward/record.url?scp=85101675385&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abd7522
DO - 10.1126/scitranslmed.abd7522
M3 - Article
C2 - 33597265
AN - SCOPUS:85101675385
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 581
M1 - eabd7522
ER -