Session: 3

PS3-03 | The role of tau in the structure and function of the axon initial segment

Cayetana Arnaiz

Laboratorio de Transporte Axonal/IBioBA/UBA

The axon initial segment (AIS) integrates synaptic signals, initiates action potentials, and acts as a selective barrier for axonal cargo. This region presents specific structural features, such as microtubule (MT) fascicles, Ankyrin-G (AnkG) and Spectrin linkers, and enrichment of ion channels. Tau, a MT-associated protein highly expressed in neurons, functions as a MT stabilizer and an axonal transport regulator. Recently, tau mutations and changes in expression levels have been associated with AIS defects. However, the molecular mechanisms by which tau modulates the AIS remain unknown. My work focuses on elucidating how tau regulates AIS structure and function. We used human neurons derived from iPSCs to perform tau conditional knockdowns (KD) and determined neuronal maturation by Sholl analysis and immunofluorescence. Interestingly, tau KD did not affect the dendritic arborization of human neurons, however AnkG revealed a distal shortening of AIS positioning. In addition, the effect of tau KD on the transport of the amyloid-precursor protein within the AIS was evaluated by live-imaging. Our preliminary results show that the techniques developed are suitable for our model and that we can quantify dynamic parameters as a readout of proper AIS function and structure. This work will provide knowledge on how tau modulates the AIS, which is essential for understanding the pathological tau effects associated with tauopathies.