Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model

Author(s): 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 X. Santos, Franz Theuring, Charles R. Harrington, Claude M. Wischik*

Journal Name: Current Alzheimer Research

Volume 17 , Issue 3 , 2020

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Abstract:

Background: Symptomatic treatments of Alzheimer’s Disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of 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 an 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 (ChAT) 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, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wild-type mice.

Conclusion: The interference with the 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 reduces a broad range of treatment responses to LMTM associated with a 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 the 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.

Keywords: Tau aggregation inhibitor, hydromethylthionine, mouse model, Alzheimer’s disease, tauopathy, acetylcholinesterase inhibitor (AChEI), drug interaction, synaptic proteins.

[1]
Sarter M, Lustig C, Blakely RD, Koshy Cherian A. Cholinergic genetics of visual attention: Human and mouse choline transporter capacity variants influence distractibility. J Physiol Paris 2016; 110(1-2): 10-8.
[http://dx.doi.org/10.1016/j.jphysparis.2016.07.001] [PMID: 27404793]
[2]
Botly LC, De Rosa E. Cholinergic influences on feature binding. Behav Neurosci 2007; 121(2): 264-76.
[http://dx.doi.org/10.1037/0735-7044.121.2.264] [PMID: 17469916]
[3]
Botly LC, De Rosa E. A cross-species investigation of acetylcholine, attention, and feature binding. Psychol Sci 2008; 19(11): 1185-93.
[http://dx.doi.org/10.1111/j.1467-9280.2008.02221.x] [PMID: 19076492]
[4]
Robinson L, Platt B, Riedel G. Involvement of the cholinergic system in conditioning and perceptual memory. Behav Brain Res 2011; 221(2): 443-65.
[http://dx.doi.org/10.1016/j.bbr.2011.01.055] [PMID: 21315109]
[5]
Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 2010; 34(8): 1307-50.
[http://dx.doi.org/10.1016/j.neubiorev.2010.04.001] [PMID: 20398692]
[6]
Ding Z, Brown JW, Rueter LE, Mohler EG. Profiling attention and cognition enhancing drugs in a rat touchscreen-based continuous performance test. Psychopharmacology (Berl) 2018; 235(4): 1093-105.
[http://dx.doi.org/10.1007/s00213-017-4827-y] [PMID: 29332255]
[7]
Gastambide F, Cotel MC, Gilmour G, O’Neill MJ, Robbins TW, Tricklebank MD. Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. Neuropsychopharmacology 2012; 37(4): 1057-66.
[http://dx.doi.org/10.1038/npp.2011.298] [PMID: 22129780]
[8]
Courtney C, Farrell D, Gray R, et al. AD2000 Collaborative Group.Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004; 363(9427): 2105-15.
[http://dx.doi.org/10.1016/S0140-6736(04)16499-4] [PMID: 15220031]
[9]
Singh G, Thomas SK, Arcona S, Lingala V, Mithal A. Treatment persistency with rivastigmine and donepezil in a large state medicaid program. J Am Geriatr Soc 2005; 53(7): 1269-70.
[http://dx.doi.org/10.1111/j.1532-5415.2005.53384_9.x] [PMID: 16108961]
[10]
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148(5): 379-97.
[http://dx.doi.org/10.7326/0003-4819-148-5-200803040-00009] [PMID: 18316756]
[11]
Mauskopf JA, Paramore C, Lee WC, Snyder EH. Drug persistency patterns for patients treated with rivastigmine or donepezil in usual care settings. J Manag Care Pharm 2005; 11(3): 231-51.
[http://dx.doi.org/10.18553/jmcp.2005.11.3.231] [PMID: 15804207]
[12]
Koller D, Hua T, Bynum JPW. Treatment patterns with antidementia drugs in the United States Medicare Cohort Study. J Am Geriatr Soc 2016; 64(8): 1540-8.
[http://dx.doi.org/10.1111/jgs.14226] [PMID: 27341454]
[13]
Martinez C, Jones RW, Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open 2013; 3(1)e002080
[http://dx.doi.org/10.1136/bmjopen-2012-002080] [PMID: 23299113]
[14]
Krolak-Salmon P, Dubois B, Sellal F, et al. France will no more reimburse available symptomatic drugs against Alzheimer’s disease. J Alzheimers Dis 2018; 66(2): 425-7.
[http://dx.doi.org/10.3233/JAD-180843] [PMID: 30282371]
[15]
Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15(5): 455-532.
[http://dx.doi.org/10.1016/S1474-4422(16)00062-4] [PMID: 26987701]
[16]
Lanctôt KL, Rajaram RD, Herrmann N. Therapy for Alzheimer’s disease: how effective are current treatments? Ther Adv Neurol Disorder 2009; 2(3): 163-80.
[http://dx.doi.org/10.1177/1756285609102724] [PMID: 21179526]
[17]
Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6(4): 37.
[http://dx.doi.org/10.1186/alzrt269] [PMID: 25024750]
[18]
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019; 15(2): 73-88.
[http://dx.doi.org/10.1038/s41582-018-0116-6] [PMID: 30610216]
[19]
Wischik CM, Schelter BO, Wischik DJ, Storey JMD, Harrington CR. Modeling prion-like processing of tau protein in Alzheimer’s disease for pharmaceutical development. J Alzheimers Dis 2018; 62(3): 1287-303.
[http://dx.doi.org/10.3233/JAD-170727] [PMID: 29226873]
[20]
Harrington CR, Storey JMD, Clunas S, et al. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer’s disease. J Biol Chem 2015; 290(17): 10862-75.
[http://dx.doi.org/10.1074/jbc.M114.616029] [PMID: 25759392]
[21]
Baddeley TC, McCaffrey J, Storey JMD, et al. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J Pharmacol Exp Ther 2015; 352(1): 110-8.
[http://dx.doi.org/10.1124/jpet.114.219352] [PMID: 25320049]
[22]
Al-Hilaly YK, Pollack SJ, Rickard JE, et al. Cysteine-independent inhibition of Alzheimer’s disease-like paired helical filament assembly by leuco-methylthioninium (LMT). J Mol Biol 2018; 430(21): 4119-31.
[http://dx.doi.org/10.1016/j.jmb.2018.08.010] [PMID: 30121297]
[23]
Melis V, Magbagbeolu M, Rickard JE, et al. Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol 2015; 26(4): 353-68.
[http://dx.doi.org/10.1097/FBP.0000000000000133] [PMID: 25769090]
[24]
Wischik CM, Edwards PC, Lai RYK, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA 1996; 93(20): 11213-8.
[http://dx.doi.org/10.1073/pnas.93.20.11213] [PMID: 8855335]
[25]
Atamna H, Mackey J, Dhahbi JM. Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction. Biofactors 2012; 38(2): 158-66.
[http://dx.doi.org/10.1002/biof.197] [PMID: 22419586]
[26]
Atamna H, Nguyen A, Schultz C, et al. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J 2008; 22(3): 703-12.
[http://dx.doi.org/10.1096/fj.07-9610com] [PMID: 17928358]
[27]
Gureev AP, Shaforostova EA, Popov VN, Starkov AA. Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria. FEBS Lett 2019; 593(5): 499-503.
[http://dx.doi.org/10.1002/1873-3468.13332] [PMID: 30734287]
[28]
Stack C, Jainuddin S, Elipenahli C, et al. Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet 2014; 23(14): 3716-32.
[http://dx.doi.org/10.1093/hmg/ddu080] [PMID: 24556215]
[29]
Zhao M, Liang F, Xu H, Yan W, Zhang J. Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting autophagy and inhibiting microglial activation. Mol Med Rep 2016; 13(1): 13-20.
[http://dx.doi.org/10.3892/mmr.2015.4551] [PMID: 26572258]
[30]
Congdon EE, Wu JW, Myeku N, et al. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 2012; 8(4): 609-22.
[http://dx.doi.org/10.4161/auto.19048] [PMID: 22361619]
[31]
Schirmer RH, Adler H, Pickhardt M, Mandelkow E. “Lest we forget you--methylene blue...”. Neurobiol Aging 2011; 32(2325): e7-e16.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.12.012]
[32]
Oz M, Lorke DE, Petroianu GA. Methylene blue and Alzheimer’s disease. Biochem Pharmacol 2009; 78(8): 927-32.
[http://dx.doi.org/10.1016/j.bcp.2009.04.034] [PMID: 19433072]
[33]
Wilcock GK, Gauthier S, Frisoni GB, et al. Potential of low dose leuco-methylthioninium bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase 3 clinical trial. J Alzheimers Dis 2018; 61(1): 435-57.
[http://dx.doi.org/10.3233/JAD-170560] [PMID: 29154277]
[34]
Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 2016; 388(10062): 2873-84.
[http://dx.doi.org/10.1016/S0140-6736(16)31275-2] [PMID: 27863809]
[35]
Schelter BO, Shiells H, Baddeley TC, et al. Concentration-dependent activity of hydromethylthionine on cognitive decline and brain atrophy in mild to moderate Alzheimer’s disease. J Alzheimers Dis 2019; 72(3): 931-46.
[http://dx.doi.org/10.3233/JAD-190772] [PMID: 31658058]
[36]
Melis V, Zabke C, Stamer K, et al. Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration. Cell Mol Life Sci 2015; 72(11): 2199-222.
[http://dx.doi.org/10.1007/s00018-014-1804-z] [PMID: 25523019]
[37]
Wischik CM, Novak M, Thøgersen HC, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; 85(12): 4506-10.
[http://dx.doi.org/10.1073/pnas.85.12.4506] [PMID: 3132715]
[38]
Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; 85(13): 4884-8.
[http://dx.doi.org/10.1073/pnas.85.13.4884] [PMID: 2455299]
[39]
Fitzpatrick AWP, Falcon B, He S, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 2017; 547(7662): 185-90.
[http://dx.doi.org/10.1038/nature23002] [PMID: 28678775]
[40]
Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. New York: Academic Press 2012.
[41]
Niewiadomska G, Komorowski S, Baksalerska-Pazera M. Amelioration of cholinergic neurons dysfunction in aged rats depends on the continuous supply of NGF. Neurobiol Aging 2002; 23(4): 601-13.
[http://dx.doi.org/10.1016/S0197-4580(01)00345-1] [PMID: 12009509]
[42]
Schwab K, Frahm S, Horsley D, et al. A protein aggregation inhibitor, leuco-methylthioninium bis(hydromethanesulfonate), decreases α-synuclein inclusions in a transgenic mouse model of synucleinopathy. Front Mol Neurosci 2018; 10: 447.
[http://dx.doi.org/10.3389/fnmol.2017.00447] [PMID: 29375308]
[43]
Abercrombie M. Estimation of nuclear population from microtome sections. Anat Rec 1946; 94: 239-47.
[http://dx.doi.org/10.1002/ar.1090940210] [PMID: 21015608]
[44]
König M, Berlin B, Schwab K, et al. Increased cholinergic response in α-synuclein transgenic mice (h-α-synL62). ACS Chem Neurosci 2019; 10(4): 1915-22.
[http://dx.doi.org/10.1021/acschemneuro.8b00274] [PMID: 30253092]
[45]
Mesulam MM. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. J Comp Neurol 2013; 521(18): 4124-44.
[http://dx.doi.org/10.1002/cne.23415] [PMID: 23852922]
[46]
Pepeu G, Grazia Giovannini M. The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Res 2017; 1670: 173-84.
[http://dx.doi.org/10.1016/j.brainres.2017.06.023] [PMID: 28652219]
[47]
Revett TJ, Baker GB, Jhamandas J, Kar S. Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci 2013; 38(1): 6-23.
[http://dx.doi.org/10.1503/jpn.110190] [PMID: 22894822]
[48]
Schneider LS, Insel PS, Weiner MW. Alzheimer’s Disease Neuroimaging Initiative.Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer’s Disease Neuroimaging Initiative. Arch Neurol 2011; 68(1): 58-66.
[http://dx.doi.org/10.1001/archneurol.2010.343] [PMID: 21220675]
[49]
Deiana S, Harrington CR, Wischik CM, Riedel G. Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl) 2009; 202(1-3): 53-65.
[http://dx.doi.org/10.1007/s00213-008-1394-2] [PMID: 19005644]
[50]
Pfaffendorf M, Bruning TA, Batnik HD, van Zwieten PA. The interaction between methylene blue and the cholinergic system. Br J Pharmacol 1997; 122(1): 95-8.
[http://dx.doi.org/10.1038/sj.bjp.0701355] [PMID: 9298533]
[51]
Devine MJ, Kittler JT. Mitochondria at the neuronal presynapse in health and disease. Nat Rev Neurosci 2018; 19(2): 63-80.
[http://dx.doi.org/10.1038/nrn.2017.170] [PMID: 29348666]
[52]
Cieri D, Vicario M, Vallese F, et al. Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca2+ handling. Biochim Biophys Acta Mol Basis Dis 2018; 1864(10): 3247-56.
[http://dx.doi.org/10.1016/j.bbadis.2018.07.011] [PMID: 30006151]
[53]
Wischik CM, Lai RYK, Harrington CR. Modelling prion-like processing of tau protein in Alzheimer’s disease for pharmaceutical development Brain Microtubule Associated Proteins: Modifications in Disease. Amsterdam: Harwood Academic Publishers 1997; pp. 185-241.
[54]
Marsh J, Alifragis P. Synaptic dysfunction in Alzheimer’s disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention. Neural Regen Res 2018; 13(4): 616-23.
[http://dx.doi.org/10.4103/1673-5374.230276] [PMID: 29722304]


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Article Details

VOLUME: 17
ISSUE: 3
Year: 2020
Page: [285 - 296]
Pages: 12
DOI: 10.2174/1567205017666200224120926

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