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I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway

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Abstract

Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I2-IRs) are increased in the brain in Alzheimer’s disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I2-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for 4 weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-d aspartate 2A and 2B receptor subunit protein levels. Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), was increased in B06-treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I2 imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP8 mice.

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Abbreviations

AD:

Alzheimer’s disease

Aldh2:

Aldehyde dehydrogenase 2

APP:

Amyloid precursor protein

BAD:

BCL-2-Associated agonist of cell death

Bdnf:

Brain-derived neurotrophic factor

CaMKII:

Calcium calmodulin kinase II

CaN:

Calcineurin

CDK5:

Cyclin-dependent kinase

cDNA:

Complementary DNA

CREB:

cAMP response element-binding

Ct:

Cycle threshold

Cxcl-10:

C-X-C motif chemokine ligand 10

(EAAT)2:

Excitatory amino acid transporter 2

ERK:

Extracellular signal-regulated kinase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GFAP:

Glial fibrillary acid protein

GSK3β:

Glycogen synthase kinase 3β

H2O2 :

Hydrogen peroxide

Hmox 1:

Hemoxygenase 1

I2-IR:

Imidazoline 2 receptors

Ide:

Insulin-degrading enzyme

Ifn-γ:

Interferon gamma

iNOS:

Inducible nitric oxide synthase

LTD:

Long-term depression

LTP:

Long-term potentiation

MAO:

Monoamine oxidase

mRNA:

Messenger RNA

Nep:

Neprilysin

NFATc1:

Nuclear factor of activated T-cells, cytoplasmic 1

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

NORT:

Novel object recognition test

Nrf1:

Nuclear factor-erythroid 2-related factor 1

OFT:

Open field test

OS:

Oxidative stress

p-Tau:

Hyperphosphorylated tau

PD:

Parkinson’s disease

PKA:

Protein kinase A

PP2B:

Phosphatase 2B

PVDF:

Polyvinylidene difluoride

ROS:

Reactive oxygen species

qPCR:

Real-time quantitative PCR

RT-PCR:

Reverse transcription-polymerase chain reaction

SAMP8:

Senescence-accelerated mouse prone 8

sAPPα:

Soluble APP α

sAPPβ:

Soluble APP β

SDS-PAGE:

Sodium dodecyl sulphate-polyacrylamide gel electrophoresis

SEM:

Standard error of the mean

TBS-T:

Tween 20 TBS

TBS:

Tris-buffered saline

TN:

Novel object, new location

Tnf-α:

Tumor necrosis factor alpha

TO:

Old object, old location

TrkB:

Tropomyosin-related kinase B

WB:

Western blotting

ΔΔCt:

Cycle threshold method

References

  1. Abás S, Estarellas C, Luque FJ, Escolano C. Easy access to (2-imidazolin-4-yl)phosphonates by a microwave assisted multicomponent reaction. Tetrahedron. 2015;71:2872–81. https://doi.org/10.1016/j.tet.2015.03.065.

    Article  CAS  Google Scholar 

  2. Abás S, Erdozain AM, Keller B, Rodríguez-Arévalo S, Callado LF, García-Sevilla JA, et al. Neuroprotective effects of a structurally new family of high affinity imidazoline I2 receptors ligands. ACS Chem Neurosci. 2017;8(4):737–42. https://doi.org/10.1021/acschemneuro.6b00426.

    Article  CAS  PubMed  Google Scholar 

  3. Abás S, Rodríguez-Arévalo S, Bagán A, Griñán-Ferré C, Vasilopoulou F, Brocos-Mosquera I, et al. Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease. J Med Chem. 2020 Apr 9;63(7):3610–3633. https://doi.org/10.1021/acs.jmedchem.9b02080.

  4. Akiguchi I, Pallàs M, Budka H, Akiyama H, Ueno M, Han J, et al. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology. 2017;37:293–305. https://doi.org/10.1111/neup.12373.

    Article  CAS  PubMed  Google Scholar 

  5. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13:93–110. https://doi.org/10.1007/s10339-011-0430-z.

    Article  CAS  PubMed  Google Scholar 

  6. Baumgärtel K, Mansuy IM. Neural functions of CaN in synaptic plasticity and memory. Learn Mem. 2012;19:375–84. https://doi.org/10.1101/lm.027201.112.

    Article  CAS  PubMed  Google Scholar 

  7. Bezprozvanny I, Hiesinger PR. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener. 2013;8:23. https://doi.org/10.1186/1750-1326-8-23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bousquet P, Hudson A, García-Sevilla JA, Li JX. Imidazoline receptors system: the past, the present and the future. Pharmacol Rev. 2020;72:1–30. https://doi.org/10.1124/pr.118.016311.

    Article  CAS  Google Scholar 

  9. Bradley CA, Peineau S, Taghibiglou C, Nicolas CS, Whitcomb DG, Bortolotto ZA, et al. A pivotal role of GSK3 in synaptic plasticity. Front Mol Neurosci. 2012;5:13. https://doi.org/10.3389/fnmol.2012.00013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bridi MS, Hawk JD, Chatterjee S, Safe S, Abel T. Pharmacological activators of the NR4A nuclear receptors enhance LTP in a CREB/CBP-dependent manner. Neuropsychopharmacology. 2017;42(6):1243–53. https://doi.org/10.1038/npp.2016.253.

    Article  CAS  PubMed  Google Scholar 

  11. Canudas AM, Gutierrez-Cuesta J, Rodríguez MI, Acuña-Castroviejo D, Sureda FX, Camins A, et al. Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev. 2005;126(12):1300–4.

    Article  CAS  Google Scholar 

  12. Caraveo G, Auluck PK, Whitesell L, Chung CY, Baru V, Mosharov EV, et al. Calcineurin determines toxic versus beneficial responses to alpha-synuclein. Proc Natl Acad Sci U S A. 2014;111(34):E3544–52. https://doi.org/10.1073/pnas.1413201111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Casanovas A, Olmos G, Ribera J, Boronat MA, Esquerda JE, García-Sevilla JA. Induction of reactive astrocytosis and prevention of motoneuron cell death by the I(2)-imidazoline receptor ligand LSL 60101. Br J Pharmacol. 2000;130(8):1767–76. https://doi.org/10.1038/sj.bjp.0703485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Choi DH, Yun JH, Lee J. Protective effect of the imidazoline I2 receptor agonist 2-BFI on oxidative cytotoxicity in astrocytes. Biochem Biophys Res Commun. 2018;503(4):3011–6. https://doi.org/10.1016/j.bbrc.2018.08.086.

    Article  CAS  PubMed  Google Scholar 

  15. Cummings J. Lessons learned from Alzheimer disease: clinical trials with negative outcomes. Clin Transl Sci. 2018;11:147–52. https://doi.org/10.1111/cts.12491.

    Article  PubMed  Google Scholar 

  16. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37. https://doi.org/10.1186/alzrt269.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement. 2018;4:195–214. https://doi.org/10.1016/j.trci.2018.03.009.

    Article  Google Scholar 

  18. Escolano C, Pallás M, Griñán-Ferré C, Abás S, Callado LF, García-Sevilla JA. Synthetic I2 imidazoline receptor ligands for prevention or treatment of human brain disorders. WO 2019/121853 A1, June 2019.

  19. Furman JL, Norris CM. Calcineurin and glial signaling: neuroinflammation and beyond. J Neuroinflammation. 2014;11:158. https://doi.org/10.1186/s12974-014-0158-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32:16129–40.

    Article  CAS  Google Scholar 

  21. Garau C, Miralles A, Garcia-Sevilla JA. Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain. J Psychopharmacol. 2013;27(2):123–34. https://doi.org/10.1177/0269881112450785.

    Article  CAS  PubMed  Google Scholar 

  22. García-Sevilla JA, Escribá PV, Walzer C, Bouras C, Guimón J. Imidazoline receptor proteins in brains of patients with Alzheimer’s disease. Neurosci Lett. 1998;247:95–8.

    Article  Google Scholar 

  23. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2010;18(5):459–80. https://doi.org/10.1016/S1474-4422(18)30499-X.

    Article  Google Scholar 

  24. Griñán-Ferré C, Palomera-Avalos V, Puigoriol-Illamola D, Camins A, Porquet D, Plà V, et al. Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in SAMP8, a model of accelerated senescence. Exp Gerontol. 2016a;80:57–69. https://doi.org/10.1016/j.exger.2016.03.014.

    Article  CAS  PubMed  Google Scholar 

  25. Griñán-Ferré C, Puigoriol-Illamola D, Palomera-Ávalos V. Environmental enrichment modified epigenetic mechanisms in SAMP8 mouse hippocampus by reducing oxidative stress and inflammaging and achieving neuroprotection. Front Aging Neurosci. 2016b;8:1–12.

    Article  Google Scholar 

  26. Griñán-Ferré C, Vasilopoulou F, Abàs S, Rodríguez-Arévalo S, Bagán A, Sureda FX, et al. Behavioral and cognitive improvement induced by novel imidazoline I2 receptor ligands in female SAMP8 mice. Neurotherapeutics. 2019;16:416–31. https://doi.org/10.1007/s13311-018-00681-5.

    Article  CAS  PubMed  Google Scholar 

  27. Horsley V, Pavlath GK. NFAT ubiquitous regulator of cell differentiation and adaptation. J Cell Biol. 2002;156(5):771–4. https://doi.org/10.1083/jcb.200111073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang SX, Zheng RY, Zeng JQ, Li XL, Han Z, Hou ST. Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists. Eur J Pharmacol. 2010;629(1–3):12–9. https://doi.org/10.1016/j.ejphar.2009.11.063.

    Article  CAS  PubMed  Google Scholar 

  29. Jin SM, Cho HJ, Kim YW, Hwang JY, Mook-Jung I. Aβ-induced Ca(2+) influx regulates astrocytic BACE1 expression via calcineurin/NFAT4 signals. Biochem Biophys Res Commun. 2012;425(3):649–55. https://doi.org/10.1016/j.bbrc.2012.07.123.

    Article  CAS  PubMed  Google Scholar 

  30. Kim S, Violette CJ, Ziff EB. Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant. Neurobiol Aging. 2015;36(12):3239–46. https://doi.org/10.1016/j.neurobiolaging.2015.09.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuno T, Mukai H, Ito A, Chang CD, Kishima K, Saito N, et al. Distinct cellular expression of calcineurin A alpha and A beta in rat brain. J Neurochem. 1992;58:1643–51. https://doi.org/10.1111/j.1471-4159.1992.tb10036.x.

    Article  CAS  PubMed  Google Scholar 

  32. Li JX. Imidazoline I2 receptors: an update. Pharmacol Ther. 2017;178:48–56. https://doi.org/10.1016/j.pharmthera.2017.03.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin CH, Lee CC, Gean PW. Involvement of a CaN cascade in amygdala depotentiation and quenching of fear memory. Mol Pharmacol. 2003;63:44–52. https://doi.org/10.1124/mol.63.1.44.

    Article  CAS  PubMed  Google Scholar 

  34. Liu J, Si Z, Li S, Huang Z, He Y, Zhang T, et al. Prevents cognitive impairment by inhibiting reactive astrogliosis in pilocarpine-induced status epilepticus rats. Front Cell Neurosci. 2018;11:428. https://doi.org/10.3389/fncel.2017.00428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Martin ZS, Neugebauer V, Dineley KT, Kayed R, Zhang W, Reese LC, et al. α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases. J Neurochem. 2012;120(3):440–52. https://doi.org/10.1111/j.1471-4159.2011.07576.x.

    Article  CAS  PubMed  Google Scholar 

  36. McDonald GR, Olivieri A, Ramsat RR, Holt A. On the formation and nature of the imidazoline I2 binding site on human monoamine oxidase-B. Pharmacol Res. 2010;62(6):475–88. https://doi.org/10.1016/j.phrs.2010.09.001.

    Article  CAS  PubMed  Google Scholar 

  37. Morley JE, Farr SA, Kumar VB, Armbrecht HJ. The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des. 2012;18:1123–30. https://doi.org/10.2174/138161212799315795.

    Article  CAS  PubMed  Google Scholar 

  38. Mukherjee A, Morales-Scheihing D, Gonzalez-Romero D, Green K, Taglialatela G, Soto C. CaN inhibition at the clinical phase of prion disease reduces neurodegeneration, improves behavioral alterations and increases animal survival. PLoS Pathog. 2010;6(10):e1001138. https://doi.org/10.1371/journal.ppat.1001138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mulkey RM, Endo S, Shenolikar S, Malenka RC. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994;369(6480):486–8.

    Article  CAS  Google Scholar 

  40. O’Donnell JC, Jackson JG, Robinson MB. Transient oxygen/glucose deprivation causes a delayed loss of mitochondria and increases spontaneous calcium signaling in astrocytic processes. J Neurosci. 2016;36:7109–27. https://doi.org/10.1523/JNEUROSCI.4518-15.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Olmos G, Ribera J, Garcia-Sevilla JA. Imidazoli(di)ne compounds interact with the phencyclidine site of NMDA receptors in the rat brain. Eur J Pharmacol. 1996;310(2–3):273–6.

    Article  CAS  Google Scholar 

  42. Olmos G, DeGregorio-Rocasolano N, Paz Regalado M, Gasull T, Assumpcio Boronat M, Trullas R, et al. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor. Br J Pharmacol. 1999;127(6):1317–26. https://doi.org/10.1038/sj.bjp.0702679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pallàs M. Senescence-accelerated mice P8: a tool to study brain aging and Alzheimer’s disease in a mouse model. ISRN Cell Biol. 2012;2012:1–12. https://doi.org/10.5402/2012/917167.

    Article  Google Scholar 

  44. Pleiss MM, Sompol P, Kraner SD, Mohmmad Abdul H, Furman JL, Guttmann RP, et al. Calcineurin proteolysis in astrocytes: implications for impaired synaptic function. Biochim Biophys Acta. 2016;1862(9):1521–32. https://doi.org/10.1016/j.bbadis.2016.05.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reese LC, Taglialatela G. A role of calcineurin in Alzheimer’s disease. Curr Neuropharmacol. 2011;9(4):685–92. https://doi.org/10.2174/157015911798376316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Reynolds GP, Boulton RM, Pearson SJ, Hudson AL, Nutt DJ. Imidazoline binding sites in Huntington’s and Parkinson’s disease putamen. Eur J Pharmacol. 1996;301(1-3):R19–21.

    Article  CAS  Google Scholar 

  47. Ruiz J, Martin I, Callado LF, Meana JJ, Barturen F, Garca-Sevilla JA. Non-adrenoreceptor [3H]idazoxan binding sites (I2-imidazoline sites) are increased in postmortem brain from patients with Alzheimer’s disease. Neurosci Lett. 1993;160:109–12. https://doi.org/10.1016/0304-3940(93)90925-B.

    Article  CAS  PubMed  Google Scholar 

  48. Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev. 2000;80(4):1483–521.

    Article  CAS  Google Scholar 

  49. Sée V, Loeffler JP. Oxidative stress induces neuronal death by recruiting a protease and phosphatase-gated mechanism. J Biol Chem. 2001;276(37):35049–59. https://doi.org/10.1074/jbc.M104988200.

    Article  PubMed  Google Scholar 

  50. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011;1(1):a006189. https://doi.org/10.1101/cshperspect.a006189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sheridan CM, Heist EK, Beals CR, Crabtree GR, Gardner P. 2002 protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3. J Biol Chem. 2002;277(50):48664–76. https://doi.org/10.1074/jbc.M20702920.

    Article  CAS  PubMed  Google Scholar 

  52. Sompol P, Norris C. Ca2+, astrocyte activation and calcineurin/NFAT signaling in age-related neurodegenerative diseases. Front Aging Neurosci. 2018;10:199. https://doi.org/10.3389/fnagi.2018.00199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sompol P, Furman JL, Pleiss MM, Kraner SD, Artiushin IA, Batten SR, Quintero JE, Simmerman LA, Beckett TL, Lovell MA, Murphy MP, Gerhardt GA, Norris CM. Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice. J Neurosci. 2017 37(25):6132–6148. https://doi.org/10.1523/JNEUROSCI.0877-17.2017.

  54. Su ZZ, Leszczyniecka M, Kang DC, Sarkar D, Chao W, Volsky DJ, et al. Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). Proc Natl Acad Sci U S A. 2003;100:1955–196. https://doi.org/10.1073/pnas.0136555100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sun J, Nan G. The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: a potential therapeutic target (review). Int J Mol Med. 2017;39(6):1338–46. https://doi.org/10.3892/ijmm.2017.2962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Szatmari E, Habas A, Yang P, Zheng JJ, Hagg T, Hetman M. A positive feedback loop between glycogen synthase kinase 3beta and protein phosphatase 1 after stimulation of NR2B NMDA receptors in forebrain neurons. J Biol Chem. 2004;280(45):37526–35. https://doi.org/10.1074/jbc.M502699200.

    Article  CAS  Google Scholar 

  57. Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res. 2009;34:639–59. https://doi.org/10.1007/s11064-009-9922-y.

    Article  CAS  PubMed  Google Scholar 

  58. Tyacke RJ, Myers JFM, Venkataraman A, Mick I, Turton S, Passchier J, et al. Evaluation of 11C-BU99008, a PET ligand for the imidazoline 2 binding site in human brain. J Nucl Med. 2018;59(10):1597–602. https://doi.org/10.2967/jnumed.118.208009.

    Article  CAS  PubMed  Google Scholar 

  59. Vehmas AK, Kawas CH, Stewart WF, Troncoso JC. Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging. 2003;24(2):321–31. https://doi.org/10.1016/s0197-4580(02)00090-8.

    Article  PubMed  Google Scholar 

  60. Wang Y, Tang JL, Xu X, Zhou XP, Du J, Wang X, et al. NMDA receptors inhibit axonal outgrowth by inactivating AKT and activating GSK-3β via calcineurin in cultured immature hippocampal neurons. Exp Cell Res. 2018;371(2):389–98. https://doi.org/10.1016/j.yexcr.2018.08.033.

    Article  CAS  PubMed  Google Scholar 

  61. Watanabe K, Uemura K, Asada M, Masato M, Akiyama H, Shinohama S, et al. The participation of insulin-like growth factor- binding protein 3 released by astrocytes in the pathology of Alzheimer’s disease. Mol Brain. 2015;8:82. https://doi.org/10.1186/s13041-015-0174-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wilson H, Dervenoulas G, Pagano G, Tyacke RJ, Polychronis S, Myers J, et al. Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson’s disease: an in vivo11C-BU99008 PET study. Brain. 2019;142(10):3116–28. https://doi.org/10.1093/brain/awz260.

    Article  PubMed  Google Scholar 

  63. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010;30(7):2636–49. https://doi.org/10.1523/JNEUROSCI.4456-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xiong TQ, Chen LM, Tan BH, Guo CY, Li YN, Zhang YF, et al. The effects of calcineurin inhibitor FK506 on actin cytoskeleton, neuronal survival and glial reactions after pilocarpine-induced status epilepticus in mice. Epilepsy Res. 2018;140:138–47. https://doi.org/10.1016/j.eplepsyres.2018.01.007.

    Article  CAS  PubMed  Google Scholar 

  65. Yu D, Tong L, Song G, Lin W, Zhang L, Bai W, et al. Tau binds both subunits of CaN, and binding is impaired by calmodulin. Biochim Biophys Acta. 2008;1783:2255–61. https://doi.org/10.1016/j.bbamcr.2008.06.015.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang F, Kang Z, Li W, Xiao Z, Zhou X. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer’s disease. J Clin Neurosci. 2012;19(7):946–9. https://doi.org/10.1016/j.jocn.2011.12.022.

    Article  CAS  PubMed  Google Scholar 

  67. Zhao H, Jin-Long Y, Susan XJ, Sheng-Tao H, Rong-Yuan Z. Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection. PLoS ONE. 2013;8(5):e64894. https://doi.org/10.1371/journal.pone.0064894.

    Article  CAS  Google Scholar 

  68. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, et al. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev. 2001;123:39–46. https://doi.org/10.1016/S0047-6374(01)00342-6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We strongly acknowledge the advice of Dr. Andrés G. Fernández (our mentor in the CaixaImpulse 2018 program) for invaluable advice. This study was supported by Ministerio de Economía y Competitividad of Spain and FEDER (PID2019-107991RB-I00, PID2019-106285RB-I00) and 2017SGR106 (AGAUR, Catalonia). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement CI18-00002. F.V. thanks the UB for APIF grant (UB2016); S. R.-A. to Generalitat de Catalunya, (2018FI-B-00227) and A. B. for APIF grant to Institute of Biomedicine (UB2018).

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Authors and Affiliations

  1. Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Neurociencies, University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain

    Foteini Vasilopoulou, Christian Griñán-Ferré & Mercè Pallàs

  2. Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain

    Sergio Rodríguez-Arévalo, Andrea Bagán, Sònia Abás & Carmen Escolano

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  7. Mercè Pallàs
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Contributions

CGF, MP and CE contributed to conceptualization and funding acquisition. SA, SRA and AB synthesized and purified B06. CGF and FV performed experiments and formal data analysis. CGF, CE, FV and MP wrote, reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Mercè Pallàs.

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Vasilopoulou, F., Griñán-Ferré, C., Rodríguez-Arévalo, S. et al. I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway. GeroScience 43, 965–983 (2021). https://doi.org/10.1007/s11357-020-00281-2

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