Citations 1
Unique lipid cargoes in APOE4 human brain-derived extracellular vesicles recruit cell adhesion molecules and promote tauopathy in Alzheimer’s disease
Ikezu, Tsuneya , Zhang, Zhengrong , Bao, Hanmei , Ikezu, Tadafumi C. , Melvin, Bridgette, Scholes, Clara, You, Yang , Ellison, Justice, Kanekiyo, Takahisa , DeTure, Michael , Peng, Junmin , Ikezu, Seiko , Yu, Kaiwen , Ikezu, Tadafumi, Ravula, Arun Reddy, Yang, You , Kanekiyo, Takahisa , Wszolek, Z.K. , Han, Xianlin , Peng, Junmin , Ikezu, Tsuneya , Ravula, Arun Reddy , Ellison, Justice, Wszołek, Zbigniew K. , Dickson, Dennis W.
No container title available | May 26, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Brain-derived extracellular vesicles (BDEVs) carry tau filaments and promote tau transmission in Alzheimer’s disease (AD). However, how APOE ε4 allele, a key genetic risk factor for AD, may change BDEV molecular structures thereby facilitate disease progression is poorly understood. Here we report comprehensive analyses of BDEVs isolated from human E3/3 and E4/4 AD brains with a biological multi-omics approach. E4/4 BDEVs significantly enhanced tau propagation in aged human MAPT (Tau) knock-in and APPNL-G-F: Tau double knock-in mouse brains in vivo and increased neuronal uptake and excitability in induced pluripotent stem cell-derived neurons (iNeurons) compared to E3/3 BDEVs in vitro. Notably, correlation analysis of BDEV-lipidome and proteome exhibited synergistic enrichment in unsaturated free fatty acid (FFA)18:2, a precursor of inflammatory w6 FFA, and neural cell adhesion molecule 1 (NCAM1). Treatment of iNeurons with FFA 18:2 induces NCAM1 expression, recruits tau into EVs and enhance their tau seeding activity, which is blocked by NCAM1 antibody in vitro . Finally, intracerebroventricular injection of NCAM1 antibody significantly alleviated pathological tau accumulation and glial inflammation in PS19 tauopathy mouse brains, which had previously been reported to exhibit increased level of 18:2 FFA. This highlights novel pathological mechanism in tau transfer mediated by E4/4 BDEVs and emphasizes strong therapeutic potential of targeting EV molecules in AD progression.