Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
复制标题
DOI：
10.1172/jci96429
复制
发表时间：
2018-05-01
影响因子：
15.9
通讯作者：
Holtzman, David M.
中科院分区：
文献类型：
--
作者：
Liao, Fan;Li, Aimin;Holtzman, David M.
APOE 基因的载脂蛋白 E E4 等位基因是晚发性阿尔茨海默病 (LOAD) 最强的遗传因素。有令人信服的证据表明，apoE 在很大程度上通过影响淀粉样蛋白 β (A beta) 的聚集和清除来影响阿尔茨海默病 (AD)；然而，这些发现背后的分子机制仍然很大程度上未知。在此，我们测试了抗人 apoE 抗体是否可以减少同时产生人 Aβ 和 apoE4 的小鼠的 Aβ 病理学，并研究了这些作用的机制。我们利用 APPPS1-21 小鼠与表达人 apoE4 (APPPS1-21/APOE4) 的 apoE4 敲入小鼠杂交。我们发现了一种抗人 apoE 抗体，抗人 apoE 4 (HAE-4)，它特异性识别人 apoE4 和 apoE3，并优先结合非脂化、聚集的 apoE，而不是循环中发现的脂化 apoE。 HAE-4 还与未固定脑切片和活体 APPPS1-21/APOE4 小鼠的淀粉样斑块中的 apoE 结合。当通过中枢或外周注射递送时，HAE-4 减少了 APPPS1-21/APOE4 小鼠中的 Aβ 沉积。使用腺相关病毒在大脑中表达 2 种不同的全长抗 apoE 抗体，我们发现 HAE 抗体减少了依赖于 Fc 的淀粉样蛋白积累。受体功能。这些数据支持这样的假设：apoE 介导的斑块形成的主要机制可能是 apoE 聚集的结果，因为用治疗性抗体优先靶向 apoE 聚集体可减少 Aβ 病理，并可能代表治疗 AD 的选择性方法。
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 beta (A beta) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease A beta pathology in mice producing both human A beta 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 A beta 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 Fc. 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 A beta pathology and may represent a selective approach to treat AD.