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Epigallocatechin-3-Gallate (EGCG) Improves Cognitive Deficits Aggravated by an Obesogenic Diet Through Modulation of Unfolded Protein Response in APPswe/PS1dE9 Mice

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Abstract

Epigallocatechin-3-gallate (EGCG), a catechin found in green tea, has been previously investigated for its neuroprotective effects in vitro and in vivo. In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD). C57BL/6 wild-type (WT) and APP/PS1 mice were used in this study. APP/PS1 mice were fed with a palmitic acid–enriched HFD (APP/PS1 HFD) containing 45% of fat mainly from hydrogenated coconut oil. Intraperitoneal glucose tolerance tests (IP-GTT) and insulin tolerance tests (IP-ITT) were performed. Western blot analyses were performed to analyse protein expression, and water maze and novel object recognition test were done to evaluate the cognitive process. EGCG treatment improves peripheral parameters such as insulin sensitivity or liver insulin pathway signalling, as well as central memory deficits. It also markedly increased synaptic markers and cAMP response element binding (CREB) phosphorylation rates, as a consequence of a decrease in the unfolded protein response (UPR) activation through the reduction in the activation factor 4 (ATF4) levels and posterior downregulation of protein tyrosine phosphatase 1B (PTP1B). Moreover, EGCG significantly decreased brain amyloid β (Aβ) production and plaque burden by increasing the levels of α-secretase (ADAM10). Also, it led to a reduction in neuroinflammation, as suggested by the decrease in astrocyte reactivity and toll-like receptor 4 (TLR4) levels. Collectively, evidence suggests that chronic EGCG prevents distinct neuropathological AD-related hallmarks. This study also provides novel insights into the metabolic and neurobiological mechanisms of EGCG against cognitive loss through its effects on UPR function, suggesting that this compound may be a promising disease-modifying treatment for neurodegenerative diseases.

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Abbreviations

EGCG:

Epigallocatechin-3-gallate

AD:

Alzheimer’s disease

T2DM:

Type 2 diabetes mellitus

HFD:

High fat diet

WT:

C57BL/6 wild-type

IP-GTT:

Intraperitoneal glucose tolerance tests

IP-ITT:

Insulin tolerance tests

CREB:

cAMP response element binding

UPR:

Unfolded protein response

ATF4:

Activation factor 4

PTP1B:

Protein tyrosine phosphatase 1B

Aβ:

Amyloid β

ADAM10:

A disintegrin and metalloproteinase 10

BACE1:

Beta secretase

TLR4:

Toll-like receptor 4

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Funding

This work was supported by the Spanish Ministry of Science and Innovation SAF2017-84283-R, PI2016/01, and CB06/05/0024 (CIBERNED), and European Regional Development Founds. The research team from UB and URV belongs to 2014SGR-525 from Generalitat de Catalunya. CBZ is supported by grants from CONACyT Mexico (No. 0177594) and RDCT from Grodman Academic International Specialization Stays 2018 B (University of Guadalajara Foundation USA). PRM is supported by grants 2015/26084-1 and 2017/13224-5, Sao Paulo Research Foundation (FAPESP)—Brazil.

Author information

Authors and Affiliations

  1. Departament of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain

    Miren Ettcheto, Oriol Busquets, Rubén Dario Castro-Torres & Antoni Camins

  2. Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira i Virgili, Reus, Spain

    Miren Ettcheto, Oriol Busquets, Rubén Dario Castro-Torres & Jaume Folch

  3. Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Miren Ettcheto, Amanda Cano, Oriol Busquets, Ester Verdaguer, Rubén Dario Castro-Torres, Carme Auladell, Jaume Folch & Antoni Camins

  4. Institute of Neuroscience, University of Barcelona, Barcelona, Spain

    Miren Ettcheto, Oriol Busquets, Ester Verdaguer, Rubén Dario Castro-Torres, Carme Auladell & Antoni Camins

  5. Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain

    Amanda Cano & Maria Luisa García

  6. Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain

    Amanda Cano & Maria Luisa García

  7. Department of Gerontology, Federal University of São Carlos (UFSCar), São Carlos, 13565-905, Brazil

    Patricia R. Manzine

  8. Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain

    Ester Verdaguer, Rubén Dario Castro-Torres & Carme Auladell

  9. Department of Cellular and Molecular Biology, Neuroscience Division, C.U.C.B.A., University of Guadalajara, Sierra Mojada, Col. Independencia, Guadalajara, Jalisco, México

    Rubén Dario Castro-Torres & Carlos Beas-Zarate

  10. Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile

    Jordi Olloquequi & Antoni Camins

  11. Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII 27/31, E-08028, Barcelona, Spain

    Antoni Camins

Authors
  1. Miren Ettcheto
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  2. Amanda Cano
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  3. Patricia R. Manzine
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  4. Oriol Busquets
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  5. Ester Verdaguer
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  6. Rubén Dario Castro-Torres
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  7. Maria Luisa García
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  8. Carlos Beas-Zarate
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  9. Jordi Olloquequi
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  10. Carme Auladell
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  11. Jaume Folch
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  12. Antoni Camins
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Contributions

J.F, C.A., A.C. and C. BZ. designed the experiments and wrote and edited the manuscript. M.E., AM.C., PR.M., O.B., E.V., RD. and CT. performed the experiments. E.V., M.E. and AM. C. performed the behavioural experiments. J.O. and ML.G provided the computational assessment and contributed to the data analysis and manuscript preparation. All authors read and contributed to the presentation of the paper.

Corresponding author

Correspondence to Antoni Camins.

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Ettcheto, M., Cano, A., Manzine, P.R. et al. Epigallocatechin-3-Gallate (EGCG) Improves Cognitive Deficits Aggravated by an Obesogenic Diet Through Modulation of Unfolded Protein Response in APPswe/PS1dE9 Mice. Mol Neurobiol 57, 1814–1827 (2020). https://doi.org/10.1007/s12035-019-01849-6

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  • DOI: https://doi.org/10.1007/s12035-019-01849-6

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