Dataset Information

Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

ABSTRACT: Alzheimer’s disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aβ42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of microdissected grafts, performed two months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231638 | GEO | 2024/05/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.

Dataset Information

Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets