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Instruments / Technical Area	Publication Details	Published	Actions
B23-Circular Dichroism	Circular dichroism spectroscopy identifies the β-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro David J. Townsend , Barbora Mala , Eleri Hughes , Rohanah Hussain , Giuliano Siligardi , Nigel J. Fullwood , David A. Middleton Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.0c00154 Diamond Proposal Number(s): [17645, 24138] Show Abstract ▼ 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.	Jun 2020
B23-Circular Dichroism	Heparin promotes the rapid fibrillization of a peptide with low intrinsic amyloidogenicity Jillian Madine , Hannah A. Davies , Eleri Hughes , David A. Middleton Biochemistry 52 (50), 8984 - 8992 DOI: 10.1021/bi401231u Diamond Proposal Number(s): [509088] Show Abstract ▼ Abstract: Amyloid deposits in vivo are complex mixtures composed of protein fibrils and nonfibrillar components, including polysaccharides of the glycosaminoglycan (GAG) class. It has been widely documented that GAGs influence the initiation and progress of self-assembly by several disease-associated amyloidogenic proteins and peptides in vitro. Here we investigated whether the GAG heparin can serve as a cofactor to induce amyloid-like fibril formation in a peptide predicted to have a weak propensity to aggregate and not associated with amyloid disorders. We selected the 23-residue peptide PLB(1–23), which corresponds to the acetylated cytoplasmic domain of the phospholamban transmembrane protein. PLB(1–23) remains unfolded in aqueous solution for >24 h and does not bind thioflavin T over this time period, in agreement with computer predictions that the peptide has a very low intrinsic amyloidogenicity. In the presence of low-molecular mass (5 kDa) heparin, which binds PLB(1–23) with micromolar affinity, the peptide undergoes spontaneous and rapid assembly into amyloid-like fibrils, the effect being more pronounced at pH 5.5 than at pH 7.4. At the lower pH, peptide aggregation is accompanied by a transition to a ?-sheet rich structure. These results are consistent with the polyanionic heparin serving as a scaffold to enhance aggregation by aligning the peptide molecules in the correct orientation and with the appropriate periodicity. PLB(1–23) is toxic to cells when added in isolation, and promotion of fibril formation by heparin can reduce the toxicity of this peptide, consistent with the notion that amyloid-like fibrils represent a benign end stage of fibrillization. This work provides insight into the role that heparin and other glycosaminoglycans may play in amyloid formation and provides therapeutic avenues targeting the reduction of cytotoxicity of species along the amyloid formation pathway.	Dec 2013

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