Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Human iPSC-derived GABAergic interneuron transplantation restores circuit balance and cognitive function in an Alzheimer's disease model.
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Zhang Xinzhe, Wang Gaojie, Chen Haodong, Sun Ye, Wangliu Ziteng, Wang Lijing, Sun Miao, Liu Qing, Zhang Xue
Аннотация
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.
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.