Department of Neurology; Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
Cell Biology | Mental Disorders | Nervous System Diseases | Neurology | Neuroscience and Neurobiology | Psychiatry
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.
MMP-2, MMP-9, frontotemporal dementia, iPSCs, neuronal survival, neurons, tau
DOI of Published Version
Stem Cell Reports. 2016 Sep 13;7(3):316-24. doi: 10.1016/j.stemcr.2016.08.006. Epub 2016 Sep 1. Link to article on publisher's site
Stem cell reports
Biswas M, Almeida S, Lopez-Gonzalez R, Mao W, Zhang Z, Karydas AM, Geschwind MD, Biernat J, Mandelkow E, Futai K, Miller BL, Gao F. (2016). MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations. Open Access Publications by UMass Chan Authors. https://doi.org/10.1016/j.stemcr.2016.08.006. Retrieved from https://escholarship.umassmed.edu/oapubs/2915
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