Tau-A152T linked to AD induces neuronal hyperexcitation through FYN-NMDAR in human iPSC-neurons

Tau protein has critical roles in Alzheimer's disease (AD) pathogenesis and neuronal excitation. Among tau gene mutations, A152T is reported to increase the risk of AD and neuronal excitability in mouse models. To examine the effects of tau gene mutations on neuronal excitability in human neurons, we introduced A152T or P301S mutation to induced pluripotent stem cells (iPSCs) using genome editing technology. To examine the effects of tau expression itself, we generated tau knockout or tau conjugate with a fluorescent protein. In excitatory neuronal culture, we found that the A152T mutation increases spontaneous neuronal excitation and the association of tau and Fyn. NMDAR antagonist blocked neuronal excitation in both the control and A152T neurons, indicating that the A152T mutation enhanced the intrinsic function of tau. Transcriptome analysis revealed structural changes by the A152T mutation. These data showed that the A152T tau gene mutation increases neuronal excitability through the tau-FYN-NMDAR pathway in excitatory neurons. Overall design: hiPSC-derived neurons with MAPT mutants were compared with those of WT