Unique lipid cargoes in APOE4 human brain-derived extracellular vesicles recruit cell adhesion molecules and promote tauopathy in Alzheimer's disease.

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 APP (NL-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.