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Stem Cell Reports. 2016 Sep 13;7(3):316-324. doi: 10.1016/j.stemcr.2016.08.006. Epub 2016 Sep 1.

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

Author information

1
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
5
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: fen-biao.gao@umassmed.edu.

Abstract

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.

KEYWORDS:

MMP-2; MMP-9; frontotemporal dementia; iPSCs; neuronal survival; neurons; tau

PMID:
27594586
PMCID:
PMC5032669
DOI:
10.1016/j.stemcr.2016.08.006
[Indexed for MEDLINE]
Free PMC Article

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