美国Denali治疗公司Gilbert Di Paolo等研究人员合作发现，降低脂质化ApoE受体相互作用有助于保护溶酶体中ApoE及其脂质载体的致病性。2024年11月11日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员报告了脂质化载脂蛋白（lipApoE2）与低密度脂蛋白受体（LDLR）结合受损能够避免脂质化ApoE3/E4所观察到的LDLR回收缺陷，并减少胆固醇酯（CE）的摄取。CE是与神经退行性疾病相关的脂质。
在人类神经元中，加入携带多不饱和脂肪酸（PUFA）-CE的ApoE揭示了一个等位基因系列（ApoE4 > ApoE3 > ApoE2），与脂褐素病变相关。脂褐素病变是由脂质过氧化引起的与年龄相关的溶酶体病理。
脂褐素增加了溶酶体中tau纤维的积累，并在APOE4小鼠大脑中升高，且tau病理加重。将PUFA-CE-lipApoE4注射入海马足以在野生型小鼠中诱发脂褐素病变。最后，保护性Christchurch突变也减少了LDLR结合，并表型化了ApoE2。
总的来说，这些数据显示，减少脂质化ApoE与LDLR的相互作用通过减少ApoE及其相关致病脂质的内溶酶体靶向作用的有害影响，显著降低了晚发性阿尔茨海默病（LOAD）的风险。
据悉，虽然ApoE是LOAD最强的遗传修饰因子，但其亚型依赖性风险的分子机制以及与ApoE相关的脂质的相关性仍不清楚。
附：英文原文
Title: Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes
Author: Jing L. Guo, Dylan Braun, Gabriel A. Fitzgerald, Yun-Ting Hsieh, Lionel Rougé, Alexandra Litvinchuk, Micah Steffek, Nicholas E. Propson, Catherine M. Heffner, Claire Discenza, Suk Ji Han, Anil Rana, Lukas L. Skuja, Bi Qi Lin, Elizabeth W. Sun, Sonnet S. Davis, Srijana Balasundar, Isabel Becerra, Jason C. Dugas, Connie Ha, Jennifer Hsiao-Nakamoto, Fen Huang, Shourya Jain, Jennifer E. Kung, Nicholas P.D. Liau, Cathal S. Mahon, Hoang N. Nguyen, Nathan Nguyen, Madhuja Samaddar, Yajuan Shi, David Tatarakis, Yuxi Tian, Yuda Zhu, Jung H. Suh, Thomas Sandmann, Meredith E.K. Calvert, Annie Arguello, Lesley A. Kane, Joseph W. Lewcock, David M. Holtzman, Christopher M. Koth, Gilbert Di Paolo
Issue&Volume: 2024-11-11
Abstract: While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer’s disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids.
DOI: 10.1016/j.cell.2024.10.027
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01209-1