Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes

• DOI: 10.1016/j.cell.2024.10.027
• Publication Date: 2024-11-11T15:36:28Z
• Authors: Jing L. Guo; Dylan Braun; Gabriel A. Fitzge...; 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-Na...; 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. Cal...; Annie Arguello; Lesley A. Kane; Joseph W. Lewcock; David M. Holtzman; Christopher M. Koth; Gilbert Di Paolo
• Keywords: Apolipoprotein E

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), molecular mechanisms underlying isoform-dependent risk and relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 decreases uptake cholesteryl esters (CEs), which are linked to neurodegeneration. In human neurons, addition ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 ApoE2) associated lipofuscinosis, age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased accumulation tau fibrils was elevated in APOE4 mouse brain exacerbation by pathology. Intrahippocampal injection PUFA-CE-lipApoE4 sufficient induce lipofuscinosis wild-type mice. Finally, protective Christchurch mutation also reduced phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD reducing deleterious effects endolysosomal targeting pathogenic lipids.