Details

Autor(en) / Beteiligte

• Liao, Fan
• Li, Aimin
• Xiong, Monica
• Bien-Ly, Nga
• Jiang, Hong
• Zhang, Yin
• Finn, Mary Beth
• Hoyle, Rosa
• Keyser, Jennifer
• Lefton, Katheryn B
• Robinson, Grace O
• Serrano, Javier Remolina
• Silverman, Adam P
• Guo, Jing L
• Getz, Jennifer
• Henne, Kirk
• Leyns, Cheryl Eg
• Gallardo, Gilbert
• Ulrich, Jason D
• Sullivan, Patrick M
• Lerner, Eli Paul
• Hudry, Eloise
• Sweeney, Zachary K
• Dennis, Mark S
• Hyman, Bradley T
• Watts, Ryan J
• Holtzman, David M

Titel

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation

Ist Teil von

• The Journal of clinical investigation, 2018-05, Vol.128 (5), p.2144-2155

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2018

Quelle

Elektronische Zeitschriftenbibliothek - Freely accessible e-journals

Beschreibungen/Notizen

• 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 β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ 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 Aβ 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 Aβ pathology and may represent a selective approach to treat AD.