Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP inTau-/-mice.
Vargas-Caballero M., Denk F., Wobst HJ., Arch E., Pegasiou C-M., Oliver PL., Shipton OA., Paulsen O., Wade-Martins R.
Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of humanMAPTcan restore Aβ-mediated inhibition on a mouseTau-/-background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full humanMAPTlocus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on aTau-/-background. We found that the human wild-typeMAPTH1 locus was able to restore Aβ42-mediated impairment of LTP. In contrast, Aβ42did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that humanMAPTis able to restore Aβ42-mediated inhibition of LTP inTau-/-mice. These results provide further evidence that tau protein is central to Aβ-induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.