Circular dichroism spectroscopy identifies the β-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro.

Middleton, David and Townsend, David and Hughes, Eleri and Fullwood, Nigel and Siligardi, Giuliano and Hussain, Rohanah and Mala, Bara (2020) Circular dichroism spectroscopy identifies the β-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro. ACS Chemical Neuroscience. ISSN 1948-7193

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Abstract

Potential drug treatments for Alzheimer’s disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilisation and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism (HT-SRCD) as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 compounds screened. Subsequently, we tested chemically-similar phenolamine drugs from the β-adrenergic receptor (βAR) agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro. Dobutamine reduces both the rate and yield of tau filament formation over 24 hours, although it has little effect on the structural transition of tau into β-sheet structures over 24 hours. Salbutamol also reduces the yield and rate of filament formation, and additionally inhibits tau’s structural change into β-sheet rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for in vivo evaluation of pre-existing β-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition in AD.