Role of Tau in Microtubule Stability in Adult Neurons

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PROJECT SUMMARY / ABSTRACT Tau, a fibrous microtubule-associated protein concentrated in the axon, binds to microtubules, thereby influencing its properties. For decades, the prevailing theory has been that tau stabilizes microtubules in the axon. This is based on test tube studies showing that excess tau can indeed stabilize microtubules, as well as overexpression studies showing this to be the case in non-neuronal cells as well. Disease researchers are so invested in the idea of tau as a microtubule stabilizer that work is underway to use microtubule-stabilizing drugs to treat diseases such as Alzheimer’s, in which tau loses its association with microtubules. Recent published work of the Principal Investigator has challenged this dogma, building on evidence that tau is enriched on the labile domains of microtubules in the axon than on the stable domains. Moreover, in that work, when tau was depleted from the neuron with RNA interference, there was a loss of microtubule mass but not due to destabilization of the stable domains of the microtubules. Rather, there was a preferential loss of the labile domains, with the remaining portion of the labile domains actually becoming more stable rather than less stable. Additional studies suggested that tau prevents the labile domain from becoming stable by outcompeting genuine microtubule-stabilizers such as MAP6, and also promotes the assembly of the labile domain. This is a strikingly different scenario from the one that has become so established in the scientific literature, and potentially transformational to both the basic sciences and medical sciences of tau. However, all of that work was done on developing rodent neurons in culture, with the very real possibility that the situation is not the same in adult brain. In this proposal, the Principal Investigator seeks to test whether the findings hold true in adult mouse brain, using viral-driven RNA interference to lower tau levels. From there, studies are proposed to delve into the proposed competition between tau and genuine microtubule stabilizers such as MAP6 by ectopically expressing fluorescently tagged versions of them in non-neuronal cells in which binding of these proteins to microtubules can be readily visualized. Collectively, these studies will contribute significantly to understanding of tau, a crucial protein for both normal functioning of the axon and for disease, and will open the door toward mechanism-based therapies to rectify the ill effects of tau loss-of-function in disease.