MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations

• Published in: Stem cell reports Vol. 7; no. 3; pp. 316 - 324
• Main Authors: Biswas, Md Helal U., Almeida, Sandra, Lopez-Gonzalez, Rodrigo, Mao, Wenjie, Zhang, Zhijun, Karydas, Anna, Geschwind, Michael D., Biernat, Jacek, Mandelkow, Eva-Maria, Futai, Kensuke, Miller, Bruce L., Gao, Fen-Biao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2016; Elsevier
• Subjects: Aged; Cell Death - genetics; Cell Differentiation - genetics; Cell Survival; Cellular Reprogramming; Cellular Reprogramming Techniques; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; iPSCs; Male; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; MMP-2; MMP-9; Mutation; neuronal survival; neurons; Neurons - cytology; Neurons - metabolism; tau; tau Proteins - genetics; tau Proteins - metabolism; iPSCs; MMP-2; neuronal survival; frontotemporal dementia; tau; MMP-9; neurons
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.08.006

How mutations in the microtubule-associated protein tau (MAPT) gene cause frontotemporal dementia (FTD) remains poorly understood. We generated and characterized multiple induced pluripotent stem cell (iPSC) lines from patients with MAPT IVS10+16 and tau-A152T mutations and a control subject. In cortical neurons differentiated from these and other published iPSC lines, we found that MAPT mutations do not affect neuronal differentiation but increase the 4R/3R tau ratio. Patient neurons had significantly higher levels of MMP-9 and MMP-2 and were more sensitive to stress-induced cell death. Inhibitors of MMP-9/MMP-2 protected patient neurons from stress-induced cell death and recombinant MMP-9/MMP-2 were sufficient to decrease neuronal survival. In tau-A152T neurons, inhibition of the ERK pathway decreased MMP-9 expression. Moreover, ectopic expression of 4R but not 3R tau-A152T in HEK293 cells increased MMP-9 expression and ERK phosphorylation. These findings provide insights into the molecular pathogenesis of FTD and suggest a potential therapeutic target for FTD with MAPT mutations. •New iPSC lines with MAPT p.A152T and IVS10+16 mutations are generated•MMP-2 and MMP-9 production is elevated in human neurons with MAPT mutations•Elevated MMP-2 and MMP-9 contribute to stress-induced neuronal cell death•Mutant tau increases ERK phosphorylation that activates MMP-9 expression In this article, Gao and colleagues generated multiple iPSC lines from patients with MAPT IVS10+16 and tau-A152T mutations and found that significantly higher levels of MMP-9/MMP-2 in patient neurons contribute to stress-induced neuronal cell death. 4R but not 3R tau-A152T activates ERK, which in turn increases MMP-9 expression. These results provide insights into the molecular pathogenesis of FTD.