The largest isoform of Ankyrin-G is required for lattice structure of the axon initial segment.

Alzheimer's disease (AD) is the most frequent neurodegenerative disease and a common dementia in elderly individuals. Previous studies found a strong correlation between axon initial segment (AIS) defects and AD, but it remains unclear whether AD itself changes the arrangement of AIS components, and the mechanisms by which adaptor proteins and ion channels in the AIS are disturbed in AD are not well understood. With super-resolution structured illumination microscopy (SIM) revealing axonal structures, here we imaged the lattice structure of completely assembled AIS in APP/PS1 neurons. By analyzing the images with Gaussian fitting and 1D mean autocorrelation, we found dual spacings (∼200 nm and ∼370 nm) of Ankyrin-G (AnkG), Na1.2 and βIV-spectrin in AD model APP/PS1 mice due to the low-expressed 480-kDa AnkG. To identify the roles of each AnkG isoform, two isoforms were separately expressed in neurons from AnkG conditional knockout mice. Mice rescued with 270-kDa AnkG displayed dual spacings of AnkG components in cultured neurons and impaired in spatial memory, while transgenic mice expressing 480-kDa AnkG showed a normal molecular distribution in the AIS and normal cognitive performance. Our findings provide new insight into the mechanisms underlying impaired cognition associated with neurodegenerative diseases such as AD.