Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient‐derived pluripotent cell models

• Published in: Alzheimer's & dementia Vol. 17; no. S2; pp. e058313 - n/a
• Main Authors: Minaya, Miguel, Martinez, Rita, Eteleeb, Abdallah, Cruchaga, Carlos, Harari, Oscar, Karch, Celeste M.
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.058313

Background Mutations in the microtubule‐associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD‐tau). Yet the pathogenic events linked to disease remain poorly understood. This study aimed to identify genes and pathways that lead to FTLD‐tau. Method To identify the earliest genes and pathways that are dysregulated in FTLD‐tau, we identified differentially expressed genes in RNA‐seq data generated from induced pluripotent stem cell (iPSC)–derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and brain tissue samples from progressive supranuclear palsy (PSP) and control brains. We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes. Results We identified 275 genes that were differentially expressed in iPSC–derived cortical neurons from MAPT R406W carriers compared to isogenic controls, MAPT IVS10+16 carriers compared to isogenic controls, and MAPT P301L carriers compared with isogenic controls. These commonly dysregulated genes were enriched for pathways involving synaptic function, neuronal development, and endolysosomal function. A subset of these genes were also changed in brains from human subjects with PSP compared to normal control brains. Finally, a subset of genes, enriched in glutamate receptor signaling, were altered across the mutant neurons and significantly changed with tau accumulation in a mouse model of tauopathy (Tau‐P301L mice). Conclusion 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 and point to common molecular pathways driven by 3 distinct MAPT mutations