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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(tau P301L )4510, with those expressing comparable levels of wild type human tau, rTg(tau wt )21221. rTg(tau P301L )4510 mice express the human tau P301L  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(tau wt )21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tau P301L )4510 mice and from rTg(tau wt )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(tau P301L )4510 cultures was hypophosphorylated in comparison with rTg(tau wt )21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tau P301L )4510 than in rTg(tau wt )21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tau P301L )4510 than rTg(tau wt )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.

Genotype-Specific Differences between Mouse CNS Stem Cell Lines Expressing Frontotemporal Dementia Mutant or Wild Type Human Tau