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| Status |
Public on Jul 15, 2020 |
| Title |
IPSC-derived neuronal cultures expressing the Alzheimer's disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Recently, genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer's disease (LOAD). One of them is the rare p.Arg47His (R47H) variant within triggering receptor expressed on myeloid cells 2 (TREM2), which has been shown to increase the risk for developing AD 2-3-fold. Here, we report the generation and characterization of a model of LOAD using lymphoblast-derived iPSCs from patients harbouring the R47H mutation in TREM2 (AD TREM2 iPSCs), as well as from control individuals without dementia (CON iPSCs). iPSCs efficiently differentiate into mature neuronal cultures and comparative global transcriptome analysis identified a distinct gene expression profile in AD TREM2 neuronal cultures. Furthermore, manipulation of the iPSCderived functional neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD TREM2 neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER) which emphasised ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.
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| Overall design |
The transcriptomes of human iPSC-derived neuronal cultures were compared between Aß-S8C dimer stimulation and control condition by microarray analysis (PrimeView Human Gene Expression Array, Affymetrix, Thermo Fisher Scientific).
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| Contributor(s) |
Wasco W, Soraia M, Martina B, James A |
| Citation(s) |
32630447 |
| |
| Submission date |
Jan 20, 2020 |
| Last update date |
Jul 15, 2020 |
| Contact name |
Wasco Wruck |
| E-mail(s) |
[email protected]
|
| Organization name |
Universitätsklinikum Düsseldorf
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| Street address |
Moorenstr. 5
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| City |
Düsseldorf |
| ZIP/Postal code |
40225 |
| Country |
Germany |
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| Platforms (1) |
| GPL16043 |
GeneChip® PrimeView™ Human Gene Expression Array (with External spike-in RNAs) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA602318 |
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