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

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 cor...

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Main Authors:	Md Helal U. Biswas, Sandra Almeida, Rodrigo Lopez-Gonzalez, Wenjie Mao, Zhijun Zhang, Anna Karydas, Michael D. Geschwind, Jacek Biernat, Eva-Maria Mandelkow, Kensuke Futai, Bruce L. Miller, Fen-Biao Gao
Format:	Article
Language:	English
Published:	Elsevier 2016-09-01
Series:	Stem Cell Reports
Subjects:	frontotemporal dementia iPSCs MMP-2 MMP-9 neuronal survival neurons tau
Online Access:	http://www.sciencedirect.com/science/article/pii/S2213671116301734

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spelling	doaj-9ff2ca099fab4498bf885813b17f71992020-11-24T23:42:39ZengElsevierStem Cell Reports2213-67112016-09-017331632410.1016/j.stemcr.2016.08.006MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT MutationsMd Helal U. Biswas0Sandra Almeida1Rodrigo Lopez-Gonzalez2Wenjie Mao3Zhijun Zhang4Anna Karydas5Michael D. Geschwind6Jacek Biernat7Eva-Maria Mandelkow8Kensuke Futai9Bruce L. Miller10Fen-Biao Gao11Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USAGerman Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, GermanyGerman Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, GermanyDepartment of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USAHow 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.http://www.sciencedirect.com/science/article/pii/S2213671116301734frontotemporal dementiaiPSCsMMP-2MMP-9neuronal survivalneuronstau
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Md Helal U. Biswas Sandra Almeida Rodrigo Lopez-Gonzalez Wenjie Mao Zhijun Zhang Anna Karydas Michael D. Geschwind Jacek Biernat Eva-Maria Mandelkow Kensuke Futai Bruce L. Miller Fen-Biao Gao
spellingShingle	Md Helal U. Biswas Sandra Almeida Rodrigo Lopez-Gonzalez Wenjie Mao Zhijun Zhang Anna Karydas Michael D. Geschwind Jacek Biernat Eva-Maria Mandelkow Kensuke Futai Bruce L. Miller Fen-Biao Gao MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations Stem Cell Reports frontotemporal dementia iPSCs MMP-2 MMP-9 neuronal survival neurons tau
author_facet	Md Helal U. Biswas Sandra Almeida Rodrigo Lopez-Gonzalez Wenjie Mao Zhijun Zhang Anna Karydas Michael D. Geschwind Jacek Biernat Eva-Maria Mandelkow Kensuke Futai Bruce L. Miller Fen-Biao Gao
author_sort	Md Helal U. Biswas
title	MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations
title_short	MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations
title_full	MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations
title_fullStr	MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations
title_full_unstemmed	MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations
title_sort	mmp-9 and mmp-2 contribute to neuronal cell death in ipsc models of frontotemporal dementia with mapt mutations
publisher	Elsevier
series	Stem Cell Reports
issn	2213-6711
publishDate	2016-09-01
description	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.
topic	frontotemporal dementia iPSCs MMP-2 MMP-9 neuronal survival neurons tau
url	http://www.sciencedirect.com/science/article/pii/S2213671116301734
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MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations

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