Targeting MT2 melatonin receptors as a therapeutic approach against Alzheimer’s disease

Equipe 2 : ENGRAM

Mémoire et apprentissage
Pathologies du cerveau
Chantal MATHIS
Chantal MATHIS
Céline HERAUD
Céline HERAUD
Cristina PISTONO
Cristina PISTONO
Karine HERBEAUX
Karine HERBEAUX

Early recognition memory deficits in Alzheimer’s disease (AD) are due to precocious alterations within the medial temporal lobe, especially the hippocampus. two main neuropathological hallmarks of AD are amyloid plaques mainly constituted of aggregated amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) and neurofibrillary tangles made of aggregations of abnormally phosphorylated tau protein. Current focus on the earliest stages of AD is driven by repeated failures of clinical trials testing new therapies, and key studies showing that the first signs of amyloid and tau pathologies, as well as hippocampal atrophy appear more than 15 years before diagnosis. In the AD research field, it is now widely admitted that there is a crucial need to better understand and target the earliest stages of the disease. As early diagnostic are currently being developed, preclinical studies are urgently needed to evaluate the effects of anti-AD therapies on the earliest stage of development of AD-like pathology in animal models. As current transgenic mouse models suffer from several limits, it is of prime interest to confirm the potential therapeutic value of new treatments on early memory deficits and AD-like neuropathology in a new generation of mouse model bearing normal human tau and mutated APP genes instead of the corresponding murine genes.

Produced mainly in the pineal gland, melatonin is well known for its key role in regulation of circadian rhythms through its action on two G-protein-coupled receptors, named MT1 and MT2. However, it is also considered as playing a role in neurodegenerative disease. Moreover, melatonin levels decrease in aging. Aβ was even shown to further reduce its production. Melatonin and its derivatives constitute a promising therapeutic pathway currently under preclinical and clinical evaluation. Although preclinical studies in transgenic mouse models of AD showed clear improvements of memory and reduced neuropathology, clinical trials aimed at testing melatonin on AD patients showed uneven outcomes. As found for other promising compounds, testing might have taken place too late in the disease progression. In addition, melatonin has a wide range of targets and complex pharmacokinetics. Therefore, it is of prime interest to evaluate the potential therapeutic value of more specific melatoninergic drugs on early signs of AD-like pathology in a new generation of mouse model. We have shown that chronic melatonin successfully improved recognition memory in C57BL/6J mice. In collaboration with Paul Pevet and Marie-Paule Felder, we have shown that MT2 receptor rather than MT1 receptors are involved in the beneficial effect of melatonin on memory function. This finding points towards the MT2 receptor as the molecular target for the future development of melatonin related candidate drugs. Silvia Rivara (University of Parma, Italy) will provide highly selective ligands for the MT2 receptor.

Aim 1: Using the highly selective MT2 receptor agonists our first aim will be to confirm that activation of MT2 receptors improves memory in C57BL/6J mice.

Aim 2: Our second aim is to characterize the effects of melatonin on recognition memory deficits in a new model of AD.

The significant advances provided by this project should reinforce the value of the melatonergic approach as a potent treatment of the earliest stages of AD. It will also confirm the MT2 receptor as a new target in designing new candidate drugs.

Collaborations :

 

Financements :

  • Projet « Idex 2018 Post-doctorants » de l’Université de Strasbourg

 

Publications:

  1. Mathis C (2019) The value of the object recognition paradigm in investigating animal models of Alzheimer’s disease: Advances and future directions, in. Ennaceur A and de Souza Silva M (Editors), Handbook of Object Novelty Recognition, Volume 26, Academic Press, pp. 307-330 ISBN: 9780128120125

 

  1. Mathis V, Cosquer B, Barbelivien A, Herbeaux K, Bothorel B, Sage-Ciocca D, Poirel VJ, Mathis C, Lecourtier L. The lateral habenula interacts with the hypothalamo-pituitary adrenal axis response upon stressful cognitive demand in rats. Behav Brain Res. 2018 Apr 2;341:63-70. doi: 10.1016/j.bbr.2017.12.016. Epub 2017 Dec 15.

 

  1. Cès A, Burg T, Herbeaux K, Héraud C, Bott JB, Mensah-Nyagan AG, Mathis C. Age-related vulnerability of pattern separation in C57BL/6J mice. Neurobiol Aging. 2018 Feb;62:120-129. doi: 10.1016/j.neurobiolaging.2017.10.013. Epub 2017 Oct 25.

 

  1. Douchamps V, Mathis C. A second wind for the cholinergic system in Alzheimer’s therapy. Behav Pharmacol. 2017 Apr;28(2 and 3 – Special Issue):112-123. doi: 10.1097/FBP.0000000000000300.

 

  1. Hamm V, Héraud C, Bott JB, Herbeaux K, Strittmatter C, Mathis C, Goutagny R. Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease. Sci Adv. 2017 Feb 24;3(2):e1601068. doi: 10.1126/sciadv.1601068. eCollection 2017 Feb.

 

  1. Penazzi L, Lorengel J, Sündermann F, Golovyashkina N, Marre S, Mathis CMB, Lewejohann L, Brandt R, Bakota L. DMSO modulates CNS function in a preclinical Alzheimer’s disease model. Neuropharmacology. 2017 Feb;113(Pt A):434-444. doi: 10.1016/j.neuropharm.2016.10.020. Epub 2016 Oct 20.

 

  1. Mathis V, Barbelivien A, Majchrzak M, Mathis C, Cassel JC, Lecourtier L. The Lateral Habenula as a Relay of Cortical Information to Process Working Memory. Cereb Cortex. 2017 Dec 1;27(12):5485-5495. doi: 10.1093/cercor/bhw316.

 

  1. Bott JB, Héraud C, Cosquer B, Herbeaux K, Aubert J, Sartori M, Goutagny R, Mathis C. APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input. J Neurosci. 2016 Oct 5;36(40):10472-10486.

 

  1. Fuchs F, Herbeaux K, Aufrere N, Kelche C, Mathis C, Barbelivien A*, Majchrzak M*. Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged. Learn Mem. 2016 May 18;23(6):303-12. doi: 10.1101/lm.041236.115. Print 2016 Jun.* equal contribution

 

  1. Hamm V, Héraud C, Cassel JC, Mathis C, Goutagny R. Precocious Alterations of Brain Oscillatory Activity in Alzheimer’s Disease: A Window of Opportunity for Early Diagnosis and Treatment. Front Cell Neurosci. 2015 Dec 21;9:491. doi: 10.3389/fncel.2015.00491. eCollection 2015. Review.

 

  1. Fuchs F, Cosquer B, Penazzi L, Mathis C, Kelche C, Majchrzak M*, Barbelivien A*. Exposure to an enriched environment up to middle age allows preservation of spatial memory capabilities in old age. Behav Brain Res. 2016 Feb 15;299:1-5. doi: 10.1016/j.bbr.2015.11.019. Epub 2015 Nov 28.* equal contribution

 

  1. Bott JB, Muller MA, Jackson J, Aubert J, Cassel JC, Mathis C, Goutagny R. Spatial Reference Memory is Associated with Modulation of Theta-Gamma Coupling in the Dentate Gyrus. Cereb Cortex. 2016 Sep;26(9):3744-3753. doi: 10.1093/cercor/bhv177. Epub 2015 Aug 6

 

  1. Mathis C*, Savier E*, Bott JB, Clesse D, Bevins N, Sage-Ciocca D, Geiger K, Gillet A, Laux-Biehlmann A, Goumon Y, Lacaud A, Lelièvre V, Kelche C, Cassel JC, Pfrieger FW, Reber M. Defective response inhibition and collicular noradrenaline enrichment in mice with duplicated retinotopic map in the superior colliculus. Brain Struct Funct. 2015;220(3):1573-84. doi: 10.1007/s00429-014-0745-5. Epub 2014 Mar 20.* equal contribution

 

  1. Delotterie DF, Mathis C, Cassel JC, Rosenbrock H, Dorner-Ciossek C, Marti A. Touchscreen tasks in mice to demonstrate differences between hippocampal and striatal functions. Neurobiol Learn Mem. 2015 Apr;120:16-27. doi: 10.1016/j.nlm.2015.02.007. Epub 2015 Feb 14.
  2. Klein C*, Mathis C*, Leva G, Patte-Mensah C, Cassel JC, Maitre M, Mensah-Nyagan AG. γ-Hydroxybutyrate (Xyrem) ameliorates clinical symptoms and neuropathology in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2015 Feb;36(2):832-44. doi: 10.1016/j.neurobiolaging.2014.10.003. * equal contribution

 

  1. Delotterie D, Mathis C, Cassel JC, Dorner-Ciossek C, Marti A. Optimization of touchscreen-based behavioral paradigms in mice: implications for building a battery of tasks taxing learning and memory functions. PLoS One. 2014 Jun 24;9(6):e100817. doi: 10.1371/journal.pone.0100817. eCollection 2014.

 

  1. Kroker KS*, Mathis C*, Marti A, Cassel JC, Rosenbrock H, Dorner-Ciossek C. PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition. Neurobiol Aging. 2014 Sep;35(9):2072-8. doi: 10.1016/j.neurobiolaging.2014.03.023. * equal contribution

 

  1. Bott JB, Cosquer B, Héraud C, Zerbinatti C, Kelche C, Cassel JC, Mathis C. Reduced plasticity and mild cognitive impairment-like deficits after entorhinal lesions in hAPP/APOE4 mice. Neurobiol Aging. 2013 Nov;34(11):2683-93. doi: 10.1016/j.neurobiolaging.2013.04.018. Epub 2013 May 23.

 

  1. Chatterjee S, Mizar P, Cassel R, Neidl R, Selvi BR, Mohankrishna DV, Vedamurthy BM, Schneider A, Bousiges O, Mathis C, Cassel JC, Eswaramoorthy M, Kundu TK, Boutillier AL. A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci. 2013 Jun 26;33(26):10698-712. doi: 10.1523/JNEUROSCI.5772-12.2013.

 

  1. Moreau PH, Bott JB, Zerbinatti C, Renger JJ, Kelche C, Cassel JC, Mathis C. ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice. Behav Brain Res. 2013 Apr 15;243:1-5. doi: 10.1016/j.bbr.2012.12.043. Epub 2013 Jan 3.

 

  1. Yassine N, Lazaris A, Dorner-Ciossek C, Després O, Meyer L, Maitre M, Mensah-Nyagan AG, Cassel JC, Mathis C. Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice. Neurobiol Aging. 2013 Mar;34(3):716-30. doi: 10.1016/j.neurobiolaging.2012.06.016. Epub 2012 Jul 20.

 

  1. Mathis C, Bott JB, Candusso MP, Simonin F, Cassel JC. Impaired striatum-dependent behavior in GASP-1-knock-out mice. Genes Brain Behav. 2011 Apr;10(3):299-308. doi: 10.1111/j.1601-183X.2010.00666.x. Epub 2010 Dec 15.

 

  1. Boeuf J, Trigo JM, Moreau PH, Lecourtier L, Vogel E, Cassel JC, Mathis C, Klosen P, Maldonado R, Simonin F. Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice. Eur J Neurosci. 2009 Sep;30(5):860-8. doi: 10.1111/j.1460-9568.2009.06865.x. Epub 2009 Aug 27.

 

  1. Moreau PH, Cosquer B, Jeltsch H, Cassel JC, Mathis C. Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice. Hippocampus. 2008;18(6):610-22. doi: 10.1002/hipo.20422.

 

  1. Cassel JC, Mathis C, Majchrzak M, Moreau PH, Dalrymple-Alford JC. Coexisting cholinergic and parahippocampal degeneration: a key to memory loss in dementia and a challenge for transgenic models? Neurodegener Dis. 2008;5(5):304-17. doi: 10.1159/000135615. Epub 2008 Jun 3. Review.

 

  1. Bour A, Grootendorst J, Vogel E, Kelche C, Dodart JC, Bales K, Moreau PH, Sullivan PM, Mathis C. Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks. Behav Brain Res. 2008 Nov 21;193(2):174-82. doi: 10.1016/j.bbr.2008.05.008. Epub 2008 May 18.

 

  1. Grootendorst J, Bour A, Vogel E, Kelche C, Sullivan PM, Dodart JC, Bales K, Mathis C. Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior. Behav Brain Res. 2005 Apr 15;159(1):1-14. Epub 2004 Nov 6.

 

  1. Bour A, Little S, Dodart JC, Kelche C, Mathis C. A secreted form of the beta-amyloid precursor protein (sAPP695) improves spatial recognition memory in OF1 mice. Neurobiol Learn Mem. 2004 Jan;81(1):27-38.

 

  1. Dodart JC, Mathis C, Bales KR, Paul SM. Does my mouse have Alzheimer’s disease? Genes Brain Behav. 2002 Aug;1(3):142-55. Review.

 

  1. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci. 2002 May;5(5):452-7.

 

  1. Dodart JC, Mathis C, Saura J, Bales KR, Paul SM, Ungerer A. Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiol Dis. 2000 Apr;7(2):71-85.

 

  1. Dodart JC, Mathis C, Bales KR, Paul SM, Ungerer A. Behavioral deficits in APP(V717F) transgenic mice deficient for the apolipoprotein E gene. Neuroreport. 2000 Feb 28;11(3):603-7.

 

  1. Dodart JC, Mathis C, Ungerer A. The beta-amyloid precursor protein and its derivatives: from biology to learning and memory processes. Rev Neurosci. 2000;11(2-3):75-93. Review.

 

  1. Stemmelin J, Mathis C, Ungerer A. GF 109203X, a selective inhibitor of protein kinase C, impairs retention performance in an operant task. Neuroreport. 1999 Sep 9;10(13):2805-9.

 

  1. Mathis C, Ungerer A. The retention deficit induced by (RS)-alpha-methyl-4-carboxyphenylglycine in a lever-press learning task is blocked by selective agonists of either group I or group II metabotropic glutamate receptors. Exp Brain Res. 1999 Nov;129(1):147-55.

 

  1. Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A. Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav Neurosci. 1999 Oct;113(5):982-90.

 

  1. Dodart JC, Mathis C, Bales KR, Paul SM, Ungerer A. Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Neurosci Lett. 1999 Dec 17;277(1):49-52.

 

  1. Ungerer A, Mathis C, Mélan C. Are glutamate receptors specifically implicated in some forms of memory processes? Exp Brain Res. 1998 Nov;123(1-2):45-51. Review.

 

  1. Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A. Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12683-8.

 

  1. Gershenfeld HK, Neumann PE, Mathis C, Crawley JN, Li X, Paul SM. Mapping quantitative trait loci for open-field behavior in mice. Behav Genet. 1997 May;27(3):201-10.

 

  1. Dodart JC, Mathis C, Ungerer A. Scopolamine-induced deficits in a two-trial object recognition task in mice. Neuroreport. 1997 Mar 24;8(5):1173-8.

 

  1. Meziane H, Mathis C, Paul SM, Ungerer A. The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task. Psychopharmacology (Berl). 1996 Aug;126(4):323-30.

 

  1. Mathis C, Vogel E, Cagniard B, Criscuolo F, Ungerer A. The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice. Neuropharmacology. 1996;35(8):1057-64.

 

  1. Mathis C, Neumann PE, Gershenfeld H, Paul SM, Crawley JN. Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains. Behav Genet. 1995 Nov;25(6):557-68.

 

  1. Mathis C, Paul SM, Crawley JN. The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology (Berl). 1994 Oct;116(2):201-6.

 

  1. Mathis C, Paul SM, Crawley JN.Characterization of benzodiazepine-sensitive behaviors in the A/J and C57BL/6J inbred strains of mice. Behav Genet. 1994 Mar;24(2):171-80.

 

  1. Mathis C, Lehmann J, Ungerer A. The selective protein kinase C inhibitor, NPC 15437, induces specific deficits in memory retention in mice. Eur J Pharmacol. 1992 Sep 10;220(1):107-10.

 

  1. Mathis C, Ungerer A. Comparative analysis of seizures induced by intracerebroventricular administration of NMDA, kainate and quisqualate in mice. Exp Brain Res. 1992;88(2):277-82.

 

  1. Ungerer A, Mathis C, Mélan C, De Barry J. The NMDA receptor antagonists, CPP and gamma-L-glutamyl-L-aspartate, selectively block post-training improvement of performance in a Y-maze avoidance learning task. Brain Res. 1991 May 17;549(1):59-65.

 

  1. Mathis C, de Barry J, Ungerer A. Memory deficits induced by gamma-L-glutamyl-L-aspartate and D-2-amino-6-phosphonovalerate in a Y-maze avoidance task: relationship to NMDA receptor antagonism. Psychopharmacology (Berl). 1991;105(4):546-52.

 

  1. Ungerer A, Mathis C, Melan C, De Barry J. [Role of neuroexcitatory amino acids in memory processes. Study with gamma-L-glutamyl-L-aspartic acid]. Encephale. 1990 Nov-Dec;16(6):423-9. French

 

  1. Mathis C, De Barry J, Ungerer A. NMDA antagonist properties of gamma-L-glutamyl-L-aspartate demonstrated on chemically induced seizures in mice. Eur J Pharmacol. 1990 Aug 21;185(1):53-9.