Mechanisms of anticholinesterase interference with tau aggregation inhibitor activity in a tau-transgenic mouse model

Gernot Riedel, Jochen Klein, Grazyna Niewiadomska, Constantin Kondak, Karima Schwab, Dilyara Lauer, Mandy Magbagbeolu, Marta Steczkowska, Maciej Zadrozny, Malgorzata Wydrych, Anna Cranston, Valeria Melis, Renato Coelho Dos Santos, Franz Theuring, Charles Harrington, Claude Wischik

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Abstract

Background: Symptomatic treatments with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of Alzheimer’s disease (AD). In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis(hydromethanesulfonate) (LMTM), we found significant differences in treatment response according to whether patients were taking LMTM either as monotherapy or as add-on to symptomatic treatments.
Methods: We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment of tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We have measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex IV activity, tau pathology and choline acetyltransferase immunoreactivity.
Results: LMTM given alone increased hippocampal acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity, reduced tau pathology, restored choline acetyltransferase (ChAT) immunoreactivity in basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from reduction in tau aggregation pathology and restoration of ChAT immunoreactivity. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wildtype mice.
Conclusion: The interference with pharmacological activity of LMTM by a cholinesterase inhibitor can be reproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment with a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems and cellular compartments at multiple levels of brain function. There is therefore no single locus for the negative interaction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces compensatory homeostatic downregulation in multiple neuronal systems. This has the effect of reducing a broad range of treatment responses to LMTM associated with reduction in tau aggregation pathology. Since the interference is dictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference with other drugs tested as add-on to existing symptomatic treatment, regardless of the intended therapeutic target or mode of action. The present findings outline key results that now provide a working model to explain interference by symptomatic treatment.
Original languageEnglish
JournalCurrent Alzheimer Research
Publication statusAccepted/In press - 30 Jan 2019

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Keywords

  • Tau aggregation inhibitor
  • Leucomethylthioninium
  • Mouse model
  • Alzheimer’s disease
  • tauopathy
  • acetylcholinesterase inhibitor (AChEI)
  • drug interaction
  • synaptic proteins

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