Axodendritic sorting and pathological missorting of Tau is isoform specific and determined by axon initial segment architecture

Hans Zempel; Frank Dennissen; Yatender Kumar; Julia Luedtke; Jacek Biernat; Eva-Maria Mandelkow; Eckhard Mandelkow

doi:10.1074/jbc.M117.784702

Axodendritic sorting and pathological missorting of Tau is isoform specific and determined by axon initial segment architecture

DZNE, Germany

↵* Corresponding author; email: hans.zempel{at}dzne.de

Author contributions: YK, FD, EMM, EM and HZ conceived the study, HZ, EM, FD and EMM wrote the paper. YK conducted the experiments leading to Fig.1 and Fig.S3A,B, data was processed and illustrated by FD and HZ. FD and HZ jointly designed and conducted experiments leading to Fig.3 and Fig.7D. JB designed genetic constructs and provided critical help with molecular biology. All other experiments were conceived, conducted, processed and illustrated by JL and HZ.

Abstract

Subcellular mislocalization of the microtubule-associated protein Tau is a hallmark of Alzheimer disease (AD) and other tauopathies. Six Tau isoforms, differentiated by the presence or absence of a second repeat or of N-terminal inserts, exist in the human CNS but their physiological and pathological differences have long remained remain elusive. Here, we investigated the properties and distributions of human and rodent Tau isoforms in primary forebrain rodent neurons. We found that the Tau-Diffusion-Barrier (TDB), located within the Axon-Initial-Segment (AIS), controls retrograde (axon-to-soma) and anterograde (soma-to-axon) traffic of Tau. Tau isoforms without the N-terminal inserts were sorted efficiently into the axon. However, the longest isoform (2N4R-Tau) was partially retained in cell bodies and dendrites, where it accelerated spine and dendrite growth. The TDB (located within the AIS) was impaired when AIS components (AnkyrinG, EB1) were knocked down or when glycogen-synthase- kinase-3-β (GSK3β, an AD-associated kinase tethered to the AIS) was overexpressed. Using superresolution-nanoscopy and live-cell imaging, we observed that microtubules within the AIS appeared highly dynamic, a feature essential for the TDB. Pathomechanistically, amyloid-β insult caused cofilin activation, F-actin remodeling, and decreased microtubutule dynamics in the AIS. Concomitantly with these amyloid-β-induced disruptions, the AIS/TDB sorting function failed, causing AD-like Tau missorting. In summary, we provide evidence that the human and rodent Tau isoforms differ in axodendritic sorting and amyloid-β-induced missorting, and that the axodendritic distribution of Tau depends on AIS integrity.