MAPT Mutations Differentially impairs neuronal physiology in Patient-Derived Glutamatergic Neurons

Tauopathies are neurodegenerative diseases caused by abnormal tau metabolism, leading to neuronal dysfunction and cell death. Many MAPT mutations have been linked to pathological tau aggregation, microtubule instability, trafficking defects and synaptic dysfunction but physiological impairments caused by each variant are not fully understood. Notably, glutamatergic neurons are proposed to be particularly vulnerable in tauopathies. Here, we generated patient-derived iPSC glutamatergic neurons (I3N) using a genetic induction protocol to investigate phenotypes associated with V337M and R406W tau mutations. Analysis of fluorescent lysosome axonal transport in I3N showed that V337M,but not R406W, increased the retrograde proportion and reduced static lysosomes, without affecting anterograde proportion. However, V337M increased both the anterograde and retrograde segmental velocities, while R406W decreased the retrograde and increased anterograde segmental velocities. In addition, the axon initial segment location was impaired in V337M and R406W neurons. Finally, V337M showed reduced amplitude and frequency of calcium signals whereas R406W showed no differences, suggesting mutation-associated electrophysiological impairments. Overall, these findings reveal that V337M and R406W mutations differentially disrupt axonal transport, AIS location, and calcium signaling. These results provide a valuable platform to study and develop therapy strategies that target specific neuronal subtype.