Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms21124516
Keywords
late onset Alzheimer's disease; iPSC-derived neuronal cultures; TREM2 R47H; A beta S8C dimer
Funding
- Medical Faculty, Heinrich-Heine-University, Dusseldorf
- European Union [305299]
- University of Antwerp Research Fund
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Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer ' s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer's disease (AD) 2-3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer's disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an A beta-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an A beta-induced gene regulatory network, we were able to identify an A beta signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized 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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