{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:30:44Z","timestamp":1793723444448,"version":"4.6.1"},"reference-count":54,"publisher":"Bentham Science Publishers Ltd.","issue":"3","license":[{"start":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T00:00:00Z","timestamp":1589760000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/legalcode"}],"content-domain":{"domain":["eurekaselect.com"],"crossmark-restriction":true},"short-container-title":["CAR"],"published-print":{"date-parts":[[2020,5,18]]},"abstract":"<jats:sec>\n<jats:title>Background:<\/jats:title>\n<jats:p>Symptomatic treatments of Alzheimer\u2019s Disease (AD) with cholinesterase inhibitors\nand\/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying\npathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking\nsymptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently\ncompleted Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate)\n(LMTM), we found significant differences in treatment response according to whether patients were\ntaking LMTM either as monotherapy or as an add-on to symptomatic treatments.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods:<\/jats:title>\n<jats:p>We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment\nof tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We\nhave measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex\nIV activity, tau pathology and Choline Acetyltransferase (ChAT) immunoreactivity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results:<\/jats:title>\n<jats:p>LMTM given alone increased hippocampal Acetylcholine (ACh) levels, glutamate release from synaptosomal\npreparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity,\nreduced tau pathology, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits\nin spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these\neffects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin\nlevels were also reduced in wild-type mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion:<\/jats:title>\n<jats:p>The interference with the pharmacological activity of LMTM by a cholinesterase inhibitor can be\nreproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment\nwith a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems\nand cellular compartments at multiple levels of brain function. There is, therefore, no single locus for the negative\ninteraction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces\ncompensatory homeostatic downregulation in multiple neuronal systems. This reduces a broad range of treatment\nresponses to LMTM associated with a reduction in tau aggregation pathology. Since the interference is\ndictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference\nwith other drugs tested as add-on to the existing symptomatic treatment, regardless of the intended\ntherapeutic target or mode of action. The present findings outline key results that now provide a working\nmodel to explain interference by symptomatic treatment.<\/jats:p>\n<\/jats:sec>","DOI":"10.2174\/1567205017666200224120926","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T14:21:24Z","timestamp":1582554084000},"page":"285-296","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model"],"prefix":"10.2174","volume":"17","author":[{"given":"Gernot","family":"Riedel","sequence":"first","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacy, Goethe University, Max-von-Laue Str. 9, Frankfurt, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazyna","family":"Niewiadomska","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Kondak","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karima","family":"Schwab","sequence":"additional","affiliation":[{"name":"Charite-Institute of Pharmacology, Universit\u00e4tsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilyara","family":"Lauer","sequence":"additional","affiliation":[{"name":"Charite-Institute of Pharmacology, Universit\u00e4tsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Magbagbeolu","sequence":"additional","affiliation":[{"name":"Charite-Institute of Pharmacology, Universit\u00e4tsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Steczkowska","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Centre, 5 Pawinski Street, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Zadrozny","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Centre, 5 Pawinski Street, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Wydrych","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Centre, 5 Pawinski Street, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cranston","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Melis","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato X.","family":"Santos","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Theuring","sequence":"additional","affiliation":[{"name":"Charite-Institute of Pharmacology, Universit\u00e4tsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R.","family":"Harrington","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude M.","family":"Wischik","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"965","reference":[{"key":"ref=1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jphysparis.2016.07.001","volume":"110","author":"Sarter M.","year":"2016","unstructured":"Sarter M.; 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