Tau “islands” affects axonal transport in vitro and in vivo

• Published in: Alzheimer's & Dementia
• Main Authors: Moretto, Edoardo, Panzi, Chiara, Stuart, Skye, Huff, Emily, Rocque, Samantha De La, Schiavo, Giampietro
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2023
• Subjects: Tau Islands
• Online Access: http://dx.doi.org/10.1002/alz.083161

Abstract Background Tau is a protein abundantly expressed in neurons where it modulates the stability of axonal microtubules, thus contributing to the regulation of axonal transport of several organelles. Tau aggregates in a group of neurodegenerative diseases named tauopathies, which include frontotemporal dementia (FTD) and Alzheimer’s disease. Recent in vitro work has uncovered the existence of tau “islands”, a microtubule‐bound multimeric state of tau, which is distinct from pathological aggregates. However, whether these structures exist in intact neurons remains unclear. Method We investigated both cultured mouse neurons and mice in vivo , using immunoistochemistry, live imaging and two photon microscopy. Results we found that human tau showed regions of higher density along axons, reminiscent of tau islands. FTD‐linked mutations, known to increase pathological phosphorylation and aggregation of tau, induces larger islands, an effect that is reversed by inhibition of p38 MAPK, known to phosphorylate tau at multiple sites. Functionally, axonal transport of BDNF‐containing secretory granules is affected by FTD‐linked mutant tau as assessed both in vitro and in vivo by using a new assay based on two‐photon microscopy. Interestingly, this impairment occurred very early on, before overt tau aggregation. Inhibition of p38 MAPK was able to partially rescue the defects in axonal transport both in vitro and in vivo . Conclusion Our data suggests that tau island size regulates axonal transport, an effect dependent on tau phosphorylation. Inefficient organelles transport may have severe consequences on the activity and plasticity of neuronal circuits. The evidence that reducing tau phosphorylation by inhibiting p38 MAPK potentiated axonal transport points towards inhibition of p38 MAPK as a promising therapeutic strategy in tauopathies.