Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.
J Clin Invest
; 128(5): 2144-2155, 2018 05 01.
Article
en En
| MEDLINE
| ID: mdl-29600961
ABSTRACT
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid ß (Aß) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aß pathology in mice producing both human Aß and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aß deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aß pathology and may represent a selective approach to treat AD.
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MEDLINE
Asunto principal:
Péptidos beta-Amiloides
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Placa Amiloide
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Apolipoproteína E4
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Anticuerpos Monoclonales de Origen Murino
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Enfermedad de Alzheimer
Idioma:
En
Revista:
J Clin Invest
Año:
2018
Tipo del documento:
Article