Transplantation of hiPSC-derived pericytes rescues Alzheimer’s disease phenotypes in APOE4/4 mice through IGF2-rich apoptotic vesicles

Background Effective therapies for Alzheimer’s disease (AD) remain to be developed. APOE4 is the strongest genetic risk factor for late-onset AD. Pericyte degeneration and blood–brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in APOE4 carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for APOE4 -related BBB damage and AD phenotypes. Methods APOE 4/4 mice were treated with pericytes derived from APOE 3/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato + lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from APOE 3/3 pericytes were evaluated in APOE 4/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in APOE 4/4 mice. Results Early, multiple transplantations of pericytes derived from APOE 3/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged APOE 4/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ APOE 4/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in APOE 3/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from APOE 3/3 pericytes demonstrated distinct therapeutic effects in APOE 4/4 mice, which were reversed by IGF2 knockout. Conclusions APOE 3/3 pericytes or APOE 3/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for APOE 4-associated AD.