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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

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.

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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.

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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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Keywords

  • Epigallocatechin-3-gallate
  • Cognitive deficits
  • APPswe/PS1dE9 mice
  • Hippocampus
  • Obesity
  • Unfolded protein response