4 results on '"Horsley, D."'
Search Results
2. Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine.
- Author
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Cranston AL, Kraev I, Stewart MG, Horsley D, Santos RX, Robinson L, Dreesen E, Armstrong P, Palliyil S, Harrington CR, Wischik CM, and Riedel G
- Subjects
- Animals, Mice, Alzheimer Disease metabolism, Alzheimer Disease pathology, Disease Models, Animal, Calcium metabolism, Frontotemporal Dementia metabolism, Frontotemporal Dementia genetics, Tauopathies metabolism, Tauopathies drug therapy, Humans, Methylene Blue analogs & derivatives, tau Proteins metabolism, Mice, Transgenic, Glutamic Acid metabolism, Synaptosomes metabolism
- Abstract
Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) tauopathies. We have previously reported that two tau transgenic mouse models, L1 and L66, produce different phenotypes resembling AD and FTD, respectively. The AD-like L1 model expresses the truncated core aggregation domain of the AD paired helical filament (PHF) form of tau (tau296-390) whereas the FTD-like L66 model expresses full-length tau carrying two mutations at P301S/G335D. We have used synaptosomes isolated from these mice to investigate K
+ -evoked glutamate release and, if abnormal, to determine responsiveness to hydromethylthionine, a tau aggregation inhibitor previously shown to reduce tau pathology in these models. We report that the transgenes in these two mouse lines cause opposite abnormalities in glutamate release. Over-expression of the core tau unit in L1 produces a significant reduction in glutamate release and a loss of Ca2+ -dependency compared with wild-type control mice. Full-length mutant tau produces an increase in glutamate release that retains normal Ca2+ -dependency. Chronic pre-treatment with hydromethylthionine normalises both reduced (L1) and excessive glutamate (L66) and restores normal Ca2+ -dependency in L1 mice. This implies that both patterns of impairment are the result of tau aggregation, but that the direction and Ca2+ -dependency of the abnormality is determined by expression of the disease-specific transgene. Our results lead to the conclusion that the tauopathies need not be considered a single entity in terms of the downstream effects of pathological aggregation of tau protein. In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD., Competing Interests: Declaration of Competing Interest The sponsor was involved in the design of the study; in the collection, analysis, and interpretation of the data; and in the writing of the report. The corresponding author had full access to all the data and had final responsibility for the submission of the report for publication. C.R.H. and C.M.W. are officers in TauRx Therapeutics Ltd., an affiliate of WisTa Laboratories Ltd. G.R. has received funding from TauRx Therapeutics Ltd. D.H., C.R.H., C.M.W., and G.R. are named inventors on patents and patent applications owned by WisTa Laboratories Ltd., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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3. LETC inhibits α-Syn aggregation and ameliorates motor deficiencies in the L62 mouse model of synucleinopathy.
- Author
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Schwab K, Frahm S, Magbagbeolu M, Horsley D, Goatman EA, Melis V, Theuring F, Ishaq A, Storey JMD, Harrington CR, Wischik CM, and Riedel G
- Subjects
- Mice, Humans, Animals, alpha-Synuclein genetics, alpha-Synuclein metabolism, Mice, Transgenic, Brain metabolism, Synucleinopathies pathology, Parkinson Disease metabolism
- Abstract
Alpha-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease (PD). Here, we explored the efficacy of N,N,N',N'-tetraethyl-10H-phenothiazine-3,7-diamine dihydrochloride (LETC), a protein aggregation inhibitor, on α-Syn aggregation. In both cellular models and transgenic mice, α-Syn aggregation was achieved by the overexpression of full-length human α-Syn fused with a signal sequence peptide. α-Syn accumulated in transfected DH60.21 neuroblastoma cells and α-Syn aggregation was inhibited by LETC with an EC
50 of 0.066 ± 0.047 μM. Full-length human α-Syn overexpressing Line 62 (L62) mice accumulated neuronal α-Syn that was associated with a decreased motor performance in the open field and automated home cage. LETC, administered orally for 6 weeks at 10 mg/kg significantly decreased α-Syn-positive neurons in multiple brain regions and this resulted in a rescue of movement deficits in the open field in these mice. LETC however, did not improve activity deficits of L62 mice in the home cage environment. The results suggest that LETC may provide a potential disease modification therapy in synucleinopathies through the inhibition of α-Syn aggregation., Competing Interests: Declaration of competing interest C.R.H., C.M.W. and J.M.D.S. declare that they are officers in TauRx Therapeutics Ltd., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
4. Assays for the Screening and Characterization of Tau Aggregation Inhibitors.
- Author
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Horsley D, Rickard JE, Vorley T, Leeper MF, Wischik CM, and Harrington CR
- Subjects
- Humans, tau Proteins metabolism, Immunoassay, Biological Assay, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Tauopathies drug therapy, Tauopathies metabolism
- Abstract
Aggregation of tau protein is a pathological hallmark of Alzheimer's disease and other neurodegenerative tauopathies. Inhibition of tau aggregation may provide a method for treatment of these disorders. Methods to identify tau aggregation inhibitors (TAIs) in vitro are useful and here we describe assays for TAIs using purified recombinant tau protein fragments in a cell-free immunoassay format and in a stably transfected cell model to create a more physiological environment., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
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