Nanomagnetic-guided tau-centric protein transport in neurons - Abstract Tau proteins are critical for healthy neuronal function, which depends on (i) robust spatial organization and stabilization of the microtubules network and (ii) precise transportation of proteins and subcellular organelles from the soma to distinct neuronal compartments. In its pathological form, Tau is known to contribute to the propagation of Alzheimer’s disease at the cellular level. Precisely controlling and guiding the spatial distribution and function of Tau proteins in populations of neurons is a powerful tool, with huge potential for discovery of a strategy to non-invasively block the progression of Alzheimer’s disease. Technically this method, however, remains a challenge. In this proposal we will address this challenge with on-chip arrays of parallelized nanomagnetic force stimulation that can be targeted to the subcellular scale to manipulate organelles in ten thousand of neurons at a time with an unprecedented level of precision. In previous studies employing this technique, we have observed that Tau-5 protein distribution localized within 24 h from one side in rat cortical neurons to the opposing side when subjected to a subcellular force range of 4.5 pN to 70 pN. The underlying mechanism between forces actuation and protein transport and the interactions between size, shape, dimension of magnetic structures dominating nanomagnetic force ranges are poorly understood. A better understanding of mechanism and interaction, however, is critical for a greater adoption of this tool in the lab and for use in implantable devices. In this proposal we will first determine how size, shape and dimensions of magnetic elements impact the magnitude and directionality of nanomagnetic force stimulation at high spatiotemporal precision (SA1). Second, we will identify the spatiotemporal mechanisms underlying nanomagnetic force control in tau- centric protein transporting (SA2). It is known that intracellular forces can act either on proteins associated to ferromagnetic nanoparticles, or on actin filaments, or on the microtubules network. This results in three possible mechanisms to direct tau-centric proteins towards magnetic elements: (1) directly through dragging nanoparticles, (2) indirectly through microtubules network dynamics, or (3) indirectly through actin signaling. Our experiments will reveal or exclude potential mechanism and the outcome will significantly advance our fundamental understanding of nanomagnetic forces in tau-centric neuronal cell function.
