Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE293647 | GEO | 2026/05/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease(AD), which is closely related to tau pathology and hippocampal impairment. Given the heterogeneity of brain neurons, the precise role of different brain neurons in terms of their sensitivity to tau accumulation and contribution to AD-like social memory loss remains unclear and requires further investigation. Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic experiments, social behavioral test, hippocampal electrophysiology, immunofluorescent staining and in vivo optical fiber recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine their effects on social memory in mice. Results: By proteomic and phosphoproteomic analyses, we identified the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, not dorsal CA1 (dCA1), but vCA1, especially its excitatory and PV neurons, were fully filled with mislocated and phosphorylated tau. Overexpression of human Tau (hTau) in excitatory and PV neurons respectively mimicked AD-like tau accumulation, significantly inhibited the neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythm and time-window efficiently ameliorated tau-impaired social memory. Significantly, one-month administration of UA efficiently decreased tau accumulation via autophagy in a TFEB (transcription factor EB)-dependent manner and recovered vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1, and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for AD treatment in the future.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets