UCSF

Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Somatodendritic mislocalization of the axonal protein tau is an early sign of Alzheimer’s disease (AD) and other neurodegenerative disorders. However, the pathogenic molecular mechanisms are incompletely understood. Here we report that tau acetylation and consequent destabilization of the axon initial segment (AIS) cytoskeleton are important in the somatodendritic mislocalization of tau. AD-relevant acetylation at K274 and K281 in the microtubule (MT)-binding domain of tau reduced tau binding to MTs. In primary neuronal cultures, acetylation at these sites led to hyperdynamic MTs in the AIS, shown by live-imaging of MT mobility and fluorescence recovery after photobleaching. AIS cytoskeletal proteins, including ankyrin G and βIV-spectrin, were downregulated in AD brains and in the brains of transgenic mice expressing tauK274/281Q, which mimics acetylation. Using photoconvertible tau constructs, we found that acetylated axonal tau is mislocalized to the somatodendritic compartment. Stabilizing MTs with epothilone D to restore the cytoskeletal barrier in the AIS prevented tau mislocalization in primary neuronal cultures. These findings suggest that tau acetylation contributes to neurodegenerative disease by compromising the cytoskeletal sorting machinery in the AIS. Finally, characterization of the AIS in human iPSC-derived neurons reveals aberrant AIS location and impaired AIS plasticity in neurons with pathogenic tau mutation.