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Targeted differentiation of regional ventral neuroprogenitors and related neuronal subtypes from human pluripotent stem cells

ABSTRACT: Purpose: To find the mechanism for the differences in cell fates between the EB (embryoid body) and AD (adherent) culture conditions Methods: hESCs were cultured in different methods, and RNA-seq were generated , in triplicate, using Illumina GAIIx. The sequence reads were analyzed with Weighted gene correlation network analysis (WGCNA) and Gene Ontology (GO) and TopHat followed by Cufflinks. qRT–PCR validation was performed using TaqMan and SYBR Green assays Results: We totally found roughly 600 genes which were specifically enriched in both day 4 EB cells and day 4 EB cells treated with SB431542 and LDN193189. Meanwhile, there were around 1000 genes which showed significant higher expression in AD cells Conclusions: complex intracellular cell contexts and extracellular components work together and define the distinct differentiation potencies of the AD and EB cells upon SHH patterning.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82052 | GEO | 2016/10/15

SECONDARY ACCESSION(S): PRJNA323821

REPOSITORIES: GEO

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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.

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Targeted differentiation of regional ventral neuroprogenitors and related neuronal subtypes from human pluripotent stem cells

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