The role of microtubule network in a mouse model of Alzheimer’s disease - PROJECT SUMMARY Alterations of a microtubule-binding protein tau are one of hallmarks of Alzheimer’s disease (AD), with progressive memory loss being one of its major symptoms. Tau is a microtubule-associated protein, which stabilizes microtubules. Tau is key facilitator of neuronal transport, mediated by microtubules, and regulation of the microtubule cytoskeleton and microtubule-mediated transport is implicated in AD. A disruption of the microtubule network, which might be caused by Tau loss of function, is observed in AD, contributing to memory loss, but it is not clear what is the role of microtubule stability/instability and microtubule-mediated neuronal transport. Activity-dependent changes, including dynamic rearrangement of microtubules and strengthening of synaptic connections, are important for memory formation. Here we propose to examine how microtubule stability/instability are affected in mice modeling some of the AD mechanisms. We and others showed that activity-dependent changes in microtubule stability are critical for synapse function and memory and are disrupted in normal aging. We will focus on the role of a phospho-protein stathmin, which function to bind tubulin, disassemble microtubules and regulate microtubule dynamics is dependent on its phosphorylation. We found that stathmin regulates memory consolidation: changes in the microtubule-destabilizing activity of stathmin cause rapid biphasic shifts in microtubule stability in the hippocampus synapses following learning. Moreover, stathmin mutations disrupt learning-dependent biphasic changes in microtubule stability, synaptic localization of GluA2 subunit of AMPARs, synaptic plasticity and memory. We will examine whether stathmin- dependent and microtubule-mediated changes in GluA2 synaptic localization improve or worsen memory deficits in a tau-related AD model. Overall, our work will characterize a role in memory in an AD model for a novel activity-dependent signaling pathway where stathmin-microtubule interactions regulate microtubule- mediated GluA2 synaptic localization. We will study how stathmin may affect a tau-related AD model, Tau P301S (PS19) mice. We previously showed that stathmin deletion makes microtubules hyperstable and Stat4A makes microtubules unstable. Our hypothesis is that activity-dependent stathmin-microtubule interactions at the synapse regulate microtubule stability, GluA2 localization and memory in a Tau mouse model of Alzheimer’s disease. In Aim 1 we will study activity-dependent changes in synaptic microtubules and GluA2 in Tau P301S (PS19) mice with loss-of-function or gain-of-function stathmin mutants. In Aim 2, we will study the effects of the stathmin mutants on synaptic plasticity and memory in Tau P301S (PS19) mice. These experiments will examine whether changes in microtubule stability/instability affect memory in PS19 mice and suggest possible microtubule involvement in the development of AD memory deficits. Positive outcomes from these studies are expected to improve our understanding of pathobiology of AD and discovery of new therapeutic targets.
