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 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.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Md Helal U
MHU
Biswas
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sandra
S
Almeida
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Rodrigo
R
Lopez-Gonzalez
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Wenjie
W
Mao
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Zhijun
Z
Zhang
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Anna
A
Karydas
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Michael D
MD
Geschwind
German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Jacek
J
Biernat
German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Eva-Maria
EM
Mandelkow
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Kensuke
K
Futai
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Bruce L
BL
Miller
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: fen-biao.gao@umassmed.edu.
Fen-Biao
FB
Gao
D000368:Aged; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
C054369:MAPT protein, human; D016875:tau Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
MMP-2; MMP-9; frontotemporal dementia; iPSCs; neuronal survival; neurons; tau