Tau conditional reduction in human-derived neurons exposes novel tau-associated functions in electrical activity and axonal transport.

Abstract

Abnormal tau accumulation is the hallmark of neurodegenerative diseases, and gain-of-toxic tau function has been pointed as triggering neuronal death. From the many roles of tau some are linked to the organization of the axon initial segment (AIS) and as a direct regulator of the activity of molecular motor proteins. Strategies aimed to reduce tau arise as promising tools for therapeutic intervention, relying on tau reduction should be harmless in mature neurons. However, the functional consequences of reducing tau have not been deeply studied, neither its effect on novel tau-associated functions METHODS: Highly polarized human derived neurons in culture for 40 days were used for functional experiments after reducing tau by designed artificial microRNAs delivered by lentiviral vectors. 3 weeks after transduction neurons were tested for tau reduction by rt-PCR, ELISA and Western blots. Patch-Clamp experiments were used to analyzed their electrical properties. Immunofluorescence were performed for analyzing the AIS structure. High-resolution high-speed live imaging was measured for the amyloid precursor protein vesicle. Tau depletion reduced the neuronal voltage dependent Na and K currents and significantly impairs the generation of action potentials. AIS distance to soma and length are impaired by tau reduction. Finally, tau reduction enhances the anterograde processivity of APP vesicles and increase the high-anterograde velocity transitions with a reduced frequency in retrogrades ones. Our data revealed that tau control important mature neuronal functions that when reduced led to changes in AIS structure, reduced electrical responses, and facilitation of anterograde transport; raising relevant attention to the therapeutic strategies directed to reduce or eliminate tau from neurons.