BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse. RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function. CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.
Stuardo et al. (Tue,) studied this question.