Axon Initial Segment Pathology in Alzheimer's Disease Mouse Model Disturbs the Action Potential Initiation and Propagation

Axonal pathology has been widely reported in Alzheimer’s disease (AD). As a highly structured region in the axon, axon initial segment (AIS) plays a vital role in action potential (AP) dynamics, including initiation and propagation, closely linked to neuronal excitability and neurotransmitter release kinetics. Previously, we showed that proteins localized in the AIS were remarkably changed in neurons from APP swe /PS1 ΔE9 mice carrying familial AD mutations. However, whether the AIS defects in APP/PS1 mouse neurons affect AP dynamics is unknown. Using genetically-encoded voltage indicators (GEVIs)-based voltage imaging, we studied AP initiation and propagation in the APP/PS1 neurons. We found that APP/PS1 neurons were more sensitive to intensive stimulations. Our data suggested that AP velocities significantly decreased in neurons from APP/PS1 mice than the wild-type mice. The velocity of forward-propagating action potentials was lower when the AIS was located more distally from the soma or when the AIS had a shorter length. The velocity of back-propagating action potentials was not correlated with the location nor with the length of the AIS. These experimental results were reproduced in neuronal simulations using multi-compartment modeling, suggesting a correlation between AIS length/location change and AP propagation velocity due to the distribution of sodium channels. Taken together, Our findings provide a deep insight into the abnormality of neuronal function in AD.