Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates

Funding: This work was supported by funding from Alzheimer’s Society [345 (AS-PG-16b-010)] awarded to L.C.S. and funding M.B.M. Y.K.A.-H. is supported by WisTa Laboratories Ltd. (PAR1596). The work was supported by ARUK South Coast Network. G.B. was supported by European Molecular Biology Organisation (EMBO) Short-Term Fellowship award (EMBO-STF 7674). LCS is supported by BBSRC [BB/S003657/1]. Acknowledgments: TEM work was performed at the University of Sussex’s Electron microscopy imaging centre (EMC), funded by the School of Life Sciences, the Wellcome Trust (095605/Z/11/A, 208348/Z/17/Z) and the RM Phillips Trust. The authors thank Pascale Schellenberger for valuable support.Peer reviewedPublisher PD

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease

Acknowledgments: The authors acknowledge Mandy Magbagbeolu and Heide Lueck for excellent technical assistance and Anna Thoma for assistance in behavioural testing and maintenance of animals. This work was funded by TauRx Therapeutics Ltd., Singapore. C.R.H. and C.M.W. declare that they are officers in TauRx Therapeutics Ltd.Peer reviewedPublisher PD

Alzheimer's disease-like paired helical filament assembly from truncated tau protein is independent of disulphide cross-linking

Abstract Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into {PHFs} is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a {C322A} substitution. We show that disulphide bond formation inhibits assembly and that the {C322A} variant rapidly forms long and highly ordered PHFs

Tau (297‐391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer’s disease brain

The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer’s disease (AD) and other tauopathies. Full‐length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297‐391 known as ‘dGAE’, spontaneously forms cross‐β‐containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation

Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models

Acknowledgements The authors acknowledge the contributions of Bettina Seelhorst (histological analysis), Anna Thoma (animal care), Marlene Arthur (animal dosing) and Pierre-Henri Moreau (experimental discussions). This work was supported by TauRx Therapeutics Ltd., Singapore.Peer reviewedPublisher PD

A Protein Aggregation Inhibitor, Leuco-Methylthioninium Bis(Hydromethanesulfonate), Decreases α-Synuclein Inclusions in a Transgenic Mouse Model of Synucleinopathy

The authors acknowledge Heide Lueck for excellent technical assistance and for maintenance of animals. AMS Biotechnology generated monoclonal antibodies from recombinant α-Syn prepared by JR.Peer reviewedPublisher PD

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups