Human iPSC-derived GABAergic interneuron transplantation restores circuit balance and cognitive function in an Alzheimer's disease model.

Abstract

INTRODUCTION: Alzheimer's disease (AD) is characterized by disrupted excitatory-inhibitory (E:I) balance and impaired synaptic function, yet current treatments fail to repair these fundamental circuit impairments. METHODS: Human induced pluripotent stem cell-derived post-mitotic medial ganglionic eminence-originated inhibitory neurons (MGE-pINs) were bilaterally transplanted into the hippocampus of 10-month-old 5xFAD mice. Cell transplantation effects were assessed by behavioral analysis, electrophysiology, immunofluorescence staining, immunoblotting, and RNA sequencing analysis. RESULTS: MGE-pIN integration restored local inhibition, correcting E:I imbalance and suppressing electroencephalogram (EEG)-detected epileptiform discharges. This network recovery, underpinned by normalized receptor subunit levels and restored synaptic plasticity - as evidenced by long-term potentiation recordings, morphological analysis, and transcriptomic profiling - led to the rescue of cognitive deficits. Importantly, these functional benefits occurred independently of amyloid beta levels. DISCUSSION: The study's findings suggest that targeted interneuron replacement can reverse network dysregulation and cognitive decline in AD, underscoring the potential of cell-based modulation as a route to restore brain function in neurodegenerative disorders.