Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy

Si Jie Tang,Marius Chiasseu,Hideyuki Takahashi,Arman Fesharaki-Zadeh,Stephen M Strittmatter,Anin Luo,Annabel Chyung,Sarah Helena Nies,Levi M Smith

doi:10.1186/s40478-020-00976-9

Si Jie Tang, Marius Chiasseu + Show 7 more

Open Access

https://doi.org/10.1186/s40478-020-00976-9

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Abstract

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Highlights

The microtubule-associated protein Tau (MAPT) accumulates in the brain of numerous neurological conditions, including Alzheimer’s disease (AD), Frontotemporal Dementia, Progressive Supranuclear Palsy, and Chronic Traumatic Encephalopathy (CTE)
To achieve chronic dosing of a Fyn kinase inhibition, mice were fed a diet of food pellets supplemented with AZD0530 at a dose calculated to achieve 5 mg/kg/d of active compound based on reported average consumption [2]
Coupled with previous pharmacokinetic data demonstrating the presence of AZD0530 in the brain and cerebrospinal fluid of treated mice [27, 39], these findings demonstrate that chronic AZD0530 administration in chow achieves drug levels sufficient to achieve sustained Fyn inhibition

Summary

Introduction

The microtubule-associated protein Tau (MAPT) accumulates in the brain of numerous neurological conditions, including Alzheimer’s disease (AD), Frontotemporal Dementia, Progressive Supranuclear Palsy, and Chronic Traumatic Encephalopathy (CTE). The accumulated protein is hyperphosphorylated at multiple sites and misfolds to create paired helical filaments in neurofibrillary tangles. This accumulation is accompanied by synapse loss, gliosis, neurodegeneration and deficits of Amongst Tau-interacting proteins is the neuronallyenriched cytoplasmic tyrosine kinase, Fyn, a member of the Src family. Dendritic Tau is required to deliver Fyn to the post-synaptic density [24]. Fyn and Tau interact to modulate synapse density, behavior and

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