Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer's Model

Abstract

Antiinflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for Alzheimer's disease (AD). This study directly addressed this issue by examining the effects of intranasal administrations of hiPSC-NSC-EVs to 3-month-old 5xFAD mice. The EVs were internalized by all microglia, which led to reduced expression of multiple genes associated with disease-associated microglia, inflammasome, and interferon-1 signaling. Furthermore, the effects of hiPSC-NSC-EVs persisted for two months post-treatment in the hippocampus, evident from reduced microglial clusters, inflammasome complexes, and expression of proteins and/or genes linked to the activation of inflammasomes, p38/mitogen-activated protein kinase, and interferon-1 signaling. The amyloid-beta (Aβ) plaques, Aβ-42, and phosphorylated-tau concentrations were also diminished, leading to better cognitive and mood function in 5xFAD mice. Thus, early intervention with hiPSC-NSC-EVs in AD may help maintain better brain function by restraining the progression of adverse neuroinflammatory signaling cascades.