Suppression of tau protein expression has been shown to improve behavioral deficits in mouse models of
tauopathies, offering an attractive therapeutic approach. Experimentally this had been achieved by switching off the promoters
controlling the transgenic human tau gene (MAPT), which is not possible in human patients. The aim of the present
study was therefore to evaluate the effectiveness of small interfering RNAs (siRNAs) and their cerebral delivery to suppress
human tau expression in vivo, which might be a therapeutic option for human tauopathies. We used primary cortical
neurons of transgenic mice expressing P301S-mutated human tau and Lund human mesencephalic (LUHMES) cells to
validate the suppressive effect of siRNA in vitro. For measuring the effect in vivo, we stereotactically injected siRNA into
the brains of P301S mice to reveal the suppression of tau by immunochemistry (AT180, MC1, and CP13 antibodies). We
found that the Accell™ SMART pool siRNA against MAPT can effectively suppress tau expression in vitro and in vivo
without a specific delivery agent. The siRNA showed a moderate distribution in the hippocampus of mice after single injection.
NeuN, GFAP, Iba-1, MHC II immunoreactivities and the terminal deoxynucleotidyl transferase dUTP nick end
labeling (TUNEL) assay showed neither signs of neurotoxicity or neuroinflammation nor apoptosis when MAPT siRNA is
present in the hippocampus. Our data suggest that siRNA against MAPT can serve as a potential tool for gene therapy in
Keywords: FTDP-17-tau, in vitro, in vivo, P301S MAPT transgenic mouse, RNAi, siRNA tauopathy.
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