Genotype-specific differences between mouse CNS stem cell lines expressing frontotemporal dementia mutant or wild type human tau

Miranda E. Orr, Rose Pitstick, Brenda Canine, Karen H. Ashe, George A. Carlson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Stem cell (SC) lines that capture the genetics of disease susceptibility provide new research tools. To assess the utility of mouse central nervous system (CNS) SC-containing neurosphere cultures for studying heritable neurodegenerative disease, we compared neurosphere cultures from transgenic mice that express human tau with the P301L familial frontotemporal dementia (FTD) mutation, rTg(tauP301L)4510, with those expressing comparable levels of wild type human tau, rTg(tauwt)21221. rTg(tauP301L)4510 mice express the human tauP301L variant in their forebrains and display cellular, histological, biochemical and behavioral abnormalities similar to those in human FTD, including age-dependent differences in tau phosphorylation that distinguish them from rTg(tauwt)21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tauP301L)4510 mice and from rTg(tauwt)21221 mice. The tau genotype-specific phosphorylation patterns in neurospheres mimicked those seen in mice, validating use of neurosphere cultures as models for studying tau phosphorylation. Genotype-specific tau phosphorylation was observed in 35 independent cell lines from individual fetuses; tau in rTg(tauP301L)4510 cultures was hypophosphorylated in comparison with rTg(tauwt)21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tauP301L)4510 than in rTg(tauwt)21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tauP301L)4510 than rTg(tauwt)21221 and control cultures. Together with the recapitulation of genotype-specific phosphorylation patterns, the observation that neurosphere lines maintained their cell line-specific-differences and retained SC characteristics over several passages supports the utility of SC cultures as surrogates for analysis of cellular disease mechanisms.

Original languageEnglish (US)
Article numbere39328
JournalPloS one
Volume7
Issue number6
DOIs
StatePublished - Jun 18 2012

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Frontotemporal Dementia
Phosphorylation
dementia
Neurology
Stem cells
central nervous system
stem cells
Stem Cells
Central Nervous System
Genotype
cell lines
Cell Line
phosphorylation
mutants
genotype
mice
Cell culture
Cells
Neurodegenerative diseases
Inborn Genetic Diseases

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Genotype-specific differences between mouse CNS stem cell lines expressing frontotemporal dementia mutant or wild type human tau. / Orr, Miranda E.; Pitstick, Rose; Canine, Brenda; Ashe, Karen H.; Carlson, George A.

In: PloS one, Vol. 7, No. 6, e39328, 18.06.2012.

Research output: Contribution to journalArticle

Orr, Miranda E. ; Pitstick, Rose ; Canine, Brenda ; Ashe, Karen H. ; Carlson, George A. / Genotype-specific differences between mouse CNS stem cell lines expressing frontotemporal dementia mutant or wild type human tau. In: PloS one. 2012 ; Vol. 7, No. 6.
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