Premium
O5‐04‐04: CANDIDATE EPIGENETIC MODIFIERS OF TAU PATHOLOGICAL BURDEN IN PRIMARY AGE‐RELATED TAUOPATHY
Author(s) -
McMillan Corey T.,
Wolk David A.,
Bennett David A.,
Schneider Julie A.,
De Jager Philip L.,
Lee Eddie B.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.3016
Subject(s) - tauopathy , epigenetics , pathological , entorhinal cortex , parahippocampal gyrus , dna methylation , methylation , cpg site , neuroscience , pathology , disease , psychology , medicine , biology , genetics , hippocampus , neurodegeneration , gene , gene expression , temporal lobe , epilepsy
clinically with progressive memory loss and neuropathologically with neurofibrillary tangles that are indistinguishable from those observed in brains from Alzheimer’s disease patients. Yet, the pathogenic events linked to disease remain poorly understood. This study was aimed at identifying genes and pathways that drive to FTLD-tau. Methods: To identify the earliest genes and pathways that are dysregulated in FTLD-tau, we identified differentially expressed (DE) genes in RNA-seq data generated from induced pluripotent stem cell (iPSC)–derived cortical neurons carrying MAPT R406W and isogenic controls and followed by replication from brain tissue samples. We then identified pathological pathways and drug targets that were enriched among the replicated DE genes. Results: We identified 838 genes that were DE in iPSC–derived cortical neurons from MAPT R406W carriers compared with isogenic control neurons. We replicated a subset of these genes in brain tissues from MAPT R406W carriers. By overlapping the replicated DE genes with genes identified in a GWAS of FTD, we found that five DE genes, FAM49A, NWD2, OBSCN, PLPPR4 and SEMA3C, also harbor SNPs associated with FTD risk (P <1310). These replicated DE genes are enriched in pathways involved in phosphorylation, regulation of phospholipase activity and MAPK signaling. Tyrosine kinase inhibitors targeting some of these replicated DE genes were also identified. Conclusions:The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to model disease. Our results indicate that regulation of phospholipase activity and MAPK signaling are key pathways that lead to disease in MAPT R406W carriers. Our analyses also indicate that antiphosphorylation drugs, such as Sorafenib and Regorafenib, may neutralize some of the pathogenic events that lead to disease.