Dataset of the week -GSE102956

by Shruti Mehrotra

Our ‘Dataset of the Week’ series features publicly available omics datasets of scientific value, intending to promote data sharing and reuse.

Publication: Neuron, 2018.

This week, we feature RNA-seq profiles of three iPSC-derived brain cell types from the publication ‘APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types’(1).

Clinical Problem:

The apolipoprotein E4 (APOE4) has gained much attention in recent years as the most significant genetic risk factor for sporadic Alzheimer’s disease (sAD)(2). Conformational changes in the secretion of APOE4 proteins by astrocytes, neurons, and microglia lead to various pathological effects unique to sAD. However, prior studies have failed to evaluate the significance of APOE4 expression in brain cells in the context of humans. Researchers have used the CRISPR/Cas9 technology to produce human-induced pluripotent stem cells (hiPSCs) mimicking AD phenotypes in 3 types of brain cells to bridge this gap. The paper also explores the physiopathological effects of removing the sAD causing factor from these stem cells.

Graphical Abstract

Experimental Design for the datasets:

Parental APOE3 cells from an unaffected subject were used to generate APOE4 iPSCs using the CRISPR/Cas9 method. These cells were further differentiated into neurons, astrocytes, and microglia-like cells in replicates of 3. Further, exome-seq data (76-bp paired-end) were generated for each type of brain cells. Gene expressions underlying the cellularization were detailed using these RNA-seq datasets.

Key findings of the publication:

• APOE4 caused accelerated maturation of neurons as well as upregulated genes related to neuronal differentiation.
• Significant downregulation of the BDNF gene associated with the synaptic function was noted. This is consistent with the cognitive impairment phenotype associated with the BDNF gene in previous studies (3,4).
• A cell-specific reduction in APOE protein transcription was noted in astrocytes indicating that the APOE4 variant can impact its own transcription.
• The APOE4 variant regulates the expression of both metabolism and transport of lipids such as
  cholesterol, with potential effects on each of the three brain cell types.
• APOE4 glial cells were observed to be impaired in their ability to uptake and eliminate extracellular beta- amyloids (Aβ) peptides.

Significance of the dataset:

A PCA plot depicting clusters of iPScs from a normal individual (Purple), iPSCs derived from neurons (Olive), and iPSCs derived from astrocytes(Brown). Plot generated on Polly.

Volcano plot showing the statistical significance of several genes, including OSMR (Oncostatin M Receptor). OSMR is expressed in the glial cells and is involved with the formation of amyloids in patients with neurodegenerative diseases. Plot generated on Polly.

Links: Full Article | Dataset: GSE102956 | PMID | DOI | OmixWiki | Polly

References:

1. Lin YT., et al. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. vol. 98(6): 1141–1154 (2018).
2. Cataldo, A., et al. Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome: Differential Effects of APOE Genotype and Presenilin Mutations. The American Journal of Pathology, vol. 157(1): 277–286 (2000).
3. Zhao J., et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nature Communications. vol. 11(1): 5540 (2020).
4. Zhang L., et al. Brain-Derived Neurotrophic Factor Ameliorates Learning Deficits in a Rat Model of Alzheimer’s Disease Induced by Aβ1–42. PLoS ONE. vol. 10(4): e0122415 (2015).