Human‐Derived Induced GABAergic Progenitor Cells Improve Cognitive Function in Mice and Inhibit Astrocyte Activation with Anti‐Inflammatory Exosomes

Abstract

ObjectiveThe role of gamma‐aminobutyric acid‐ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown.MethodsHuman‐derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP).ResultsWe showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin‐1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD‐related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti‐inflammatory miRNA, inhibited astrocyte activation invitro and in vivo, and the mechanism was related to regulation of CD4+ Th1 cells mediated tumor necrosis factor (TNF) pathway.InterpretationTaken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti‐inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024;96:488–507