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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

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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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  1. Foteini Vasilopoulou
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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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