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美国格拉德斯通研究所Yadong Huang研究组的最新研究发现，APOE-R136S突变可防止载脂蛋白E4（APOE4）诱导的Tau病理学、神经变性和神经炎症。该项研究成果发表在2023年11月13日出版的《自然-神经科学》上。

研究人员探究了R136S突变是否也能保护晚发性阿尔茨海默病（LOAD）免受APOE4的影响。研究人员建立了携带人APOE4同卵或异卵R136S突变的tauopathy小鼠和人iPSC衍生神经元模型。研究发现，同源R136S突变可挽救APOE4诱导的Tau病理学、神经变性和神经炎症。杂合R136S突变可部分防止APOE4造成的神经变性和神经炎症，但不能减弱Tau病理学。单核RNA测序显示，APOE4-R136S突变以基因剂量依赖的方式增加了疾病保护细胞群，减少了疾病相关细胞群。因此，APOE-R136S突变可避免APOE4诱导的AD病理变化，为AD治疗提供了一个新靶点。

据了解，载脂蛋白E4是晚发性阿尔茨海默病最强的遗传风险因素，会导致发病年龄提前并加重病症。目前亟需确定保护性靶点。最近发现的罕见APOE变异APOE3-R136S（Christchurch）可保护PSEN1-E280A携带者免受早发性阿兹海默症的影响。

附：英文原文

Title: The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation

Author: Nelson, Maxine R., Liu, Peng, Agrawal, Ayushi, Yip, Oscar, Blumenfeld, Jessica, Traglia, Michela, Kim, Min Joo, Koutsodendris, Nicole, Rao, Antara, Grone, Brian, Hao, Yanxia, Yoon, Seo Yeon, Xu, Qin, De Leon, Samuel, Choenyi, Tenzing, Thomas, Reuben, Lopera, Francisco, Quiroz, Yakeel T., Arboleda-Velasquez, Joseph F., Reiman, Eric M., Mahley, Robert W., Huang, Yadong

Issue&Volume: 2023-11-13

Abstract: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

DOI: 10.1038/s41593-023-01480-8

Source: https://www.nature.com/articles/s41593-023-01480-8

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex