Human iPSC-Derived GABAergic Interneuron transplantation rescues circuit dysfunction and tau pathology in Alzheimer’s disease model

Alzheimer's disease (AD) pathophysiology involves disruption of excitatory-inhibitory (E: I) balance and tau accumulation, yet current therapeutic approaches fail to address these interconnected pathologies. Here, we demonstrate that transplanting post-mitotic human iPSC-derived medial ganglionic eminence-originated pallial inhibitory neurons (MGE-pINs) into the hippocampus of 5XFAD mice induces therapeutic effects on synaptic plasticity and cognition through multiple mechanistic pathways. At 6.5 months post transplantation (MPT), MGE-pINs successfully integrated into host neural circuits and restored hippocampal function by attenuating hyperexcitability (72.4% reduction in epileptiform discharges, p<0.001) and normalizing synaptic E: I balance through modulation of GABAA receptor α1/α3 subunit composition and chloride transporter expression. Strikingly, grafts selectively attenuated phosphorylated tau burden by 53-61% (p<0.0001) independent of amyloid-β clearance, while restoring both inhibitory (165.5% increase) and excitatory (65.5% increase) synapse densities (p<0.01). Transcriptomic analysis revealed calcium homeostasis and neuroplasticity pathways, correlating with spatial and working memory performance. Our study establishes a clinically translatable cell therapy that simultaneously targets circuit dysfunction and tau-driven neurodegeneration, providing a paradigm shift for AD intervention.