On 18 September, Dr Peter Dongmin Sohn and colleagues published a paper in Neuron, showing that tau proteins associated with frontotemporal dementia prevent neurons from functioning properly by sequestering EB3 proteins in the AIS region of neurons within the brain. The proper functioning of neurons is dependent on their “excitability”: their ability to create, propagate and terminate electrical signals. The axon initial segment (AIS), a specialised area located at the axon root, is where many electrical signals originate before travelling down the axon fiber. The AIS is extremely plastic: depending on the activity of the neuron, it can remodel itself, becoming longer or shorter. This “plasticity” enables normal signal propagation. However, in diseases such as frontotemporal dementia (FTD) neuronal excitability is altered - neurons become “hyperexcitable”, mis-firing electrical signals and causing cognitive dysfunction. Interestingly, recent studies suggest that tau proteins may help regulate the structure and function of the AIS. However, it is not yet clear how the mutated tau proteins associated with FTD interact with the AIS, or whether this influences the neuron ‘hyperexcitability’ that causes cognitive decline in FTD.
To investigate these questions, Dr Sohn and colleagues created an in vitromodel of FTD using human neurons derived from cells donated by people with FTD. The donor cells produce a mutated form of the tau protein, called tau. Using advanced microscopy techniques to compare the FTD neurons with healthy ones, the researchers observed that tau neurons had much shorter AIS regions. In addition, stimulation of FTD neurons did not cause any changes in AIS length or structure, as was seen in healthy neurons. Detailed analysis of electrical traces from tau neurons showed a very spiky, hyperactive pattern: the FTD neurons fired up to 6 times more often than their healthy counterparts. To try to understand how tau was causing this hyperexcitability, Dr Sohn and colleagues took a closer look at structural proteins within the AIS. They saw that tauinteracted with a protein called EB3, which helps stabilise the microtubule scaffolding within the AIS. In normal neurons, this interaction was much less strong than in tau neurons: as a result, much more EB3 was clustered in the AIS of FTD neurons compared to healthy cells. The quantity of EB3 in the AIS region was correlated with neuronal hyperexcitation: the more EB3 there was, the more electrical mis-firing occurred. Importantly, reducing EB3 restored normal function to the AIS, allowing it to elongate and shorten in response to electrical signals. Together, these results suggest that the EB3 protein might play an important role in the neuronal dysfunction that characterises FTD.