PMID- 31838720 OWN - NLM STAT- MEDLINE DCOM- 20201229 LR - 20201229 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 57 IP - 4 DP - 2020 Apr TI - Epigallocatechin-3-Gallate (EGCG) Improves Cognitive Deficits Aggravated by an Obesogenic Diet Through Modulation of Unfolded Protein Response in APPswe/PS1dE9 Mice. PG - 1814-1827 LID - 10.1007/s12035-019-01849-6 [doi] AB - 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 beta (Abeta) production and plaque burden by increasing the levels of alpha-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. FAU - Ettcheto, Miren AU - Ettcheto M AD - Departament of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. AD - Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira i Virgili, Reus, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. FAU - Cano, Amanda AU - Cano A AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. FAU - Manzine, Patricia R AU - Manzine PR AD - Department of Gerontology, Federal University of Sao Carlos (UFSCar), Sao Carlos, 13565-905, Brazil. FAU - Busquets, Oriol AU - Busquets O AD - Departament of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. AD - Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira i Virgili, Reus, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. FAU - Verdaguer, Ester AU - Verdaguer E AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. AD - Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. FAU - Castro-Torres, Ruben Dario AU - Castro-Torres RD AD - Departament of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. AD - Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira i Virgili, Reus, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. AD - Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. AD - Department of Cellular and Molecular Biology, Neuroscience Division, C.U.C.B.A., University of Guadalajara, Sierra Mojada, Col. Independencia, Guadalajara, Jalisco, Mexico. FAU - Garcia, Maria Luisa AU - Garcia ML AD - Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain. AD - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. FAU - Beas-Zarate, Carlos AU - Beas-Zarate C AD - Department of Cellular and Molecular Biology, Neuroscience Division, C.U.C.B.A., University of Guadalajara, Sierra Mojada, Col. Independencia, Guadalajara, Jalisco, Mexico. FAU - Olloquequi, Jordi AU - Olloquequi J AD - Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Talca, Chile. FAU - Auladell, Carme AU - Auladell C AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. AD - Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. FAU - Folch, Jaume AU - Folch J AD - Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira i Virgili, Reus, Spain. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. FAU - Camins, Antoni AU - Camins A AUID- ORCID: 0000-0002-1229-5956 AD - Departament of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. camins@ub.edu. AD - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. camins@ub.edu. AD - Institute of Neuroscience, University of Barcelona, Barcelona, Spain. camins@ub.edu. AD - Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Talca, Chile. camins@ub.edu. AD - Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciencies de l'Alimentacio, Universitat de Barcelona, Av. Joan XXIII 27/31, E-08028, Barcelona, Spain. camins@ub.edu. LA - eng GR - SAF2017-84283-R/Ministerio de Ciencia e Innovacion/ PT - Journal Article DEP - 20191214 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Amyloid beta-Peptides) RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - 0 (Presenilin-1) RN - 8R1V1STN48 (Catechin) RN - BQM438CTEL (epigallocatechin gallate) SB - IM MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Blood Glucose/metabolism MH - Catechin/*analogs & derivatives/chemistry/pharmacokinetics/pharmacology/therapeutic use MH - Cognitive Dysfunction/blood/complications/*drug therapy/physiopathology MH - *Diet, High-Fat MH - Hippocampus/drug effects/pathology/physiopathology MH - Insulin/metabolism MH - Liver/metabolism MH - Male MH - Memory Disorders/blood/complications/drug therapy/physiopathology MH - Mice, Inbred C57BL MH - Mice, Obese MH - Mice, Transgenic MH - Models, Biological MH - Presenilin-1/*metabolism MH - Signal Transduction MH - Spatial Learning/drug effects MH - Tissue Distribution/drug effects MH - *Unfolded Protein Response/drug effects OTO - NOTNLM OT - APPswe/PS1dE9 mice OT - Cognitive deficits OT - Epigallocatechin-3-gallate OT - Hippocampus OT - Obesity OT - Unfolded protein response EDAT- 2019/12/16 06:00 MHDA- 2020/12/30 06:00 CRDT- 2019/12/16 06:00 PHST- 2019/08/20 00:00 [received] PHST- 2019/11/27 00:00 [accepted] PHST- 2019/12/16 06:00 [pubmed] PHST- 2020/12/30 06:00 [medline] PHST- 2019/12/16 06:00 [entrez] AID - 10.1007/s12035-019-01849-6 [pii] AID - 10.1007/s12035-019-01849-6 [doi] PST - ppublish SO - Mol Neurobiol. 2020 Apr;57(4):1814-1827. doi: 10.1007/s12035-019-01849-6. Epub 2019 Dec 14.