Abstract
Alzheimer's disease (AD) fundamentally represents a metabolic disease associated with brain insulin resistance. TNF-α/c-Jun N-terminal kinase (JNK) signaling plays a central role in serine phosphorylation of insulin receptor substrate-1 (IRS-1). (-)-Epigallocatechin-3-gallate (EGCG), a potent antioxidant, has been verified to attenuate peripheral insulin resistance by reducing IRS-1 signaling blockage. This study aimed to investigate the effects and possible mechanisms of EGCG on central IRS-1 signaling in vivo. APP/PS1 mice were treated with EGCG, and spatial memory was assessed by the Morris water maze test. Levels of soluble and insoluble Aβ42 in the hippocampus were determined by ELISA. The activation of NF-α/JNK and IRS signaling was detected by immunohistochemistry and Western blot analysis. Our results showed that EGCG ameliorated the impaired learning and memory in APP/PS1 mice. Notably, we found a significant reduction of IRS-1pS636 level accompanied with decreased Aβ42 levels in the hippocampus of 13-month-old female APP/PS1 mice after treatment with EGCG (2 or 6 mg/kg/day) for 4 weeks. Furthermore, EGCG treatment inhibited TNF-α/JNK signaling and increased the phosphorylation of Akt and glycogen synthase kinase-3β in the hippocampus of APP/PS1 mice. In conclusion, our study provides evidence that long-term consumption of EGCG may alleviate AD-related cognitive deficits by effectively attenuating central insulin resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / prevention & control
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Blotting, Western
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Catechin / analogs & derivatives*
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Catechin / pharmacology
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Disease Models, Animal
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Female
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Immunohistochemistry
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Insulin Receptor Substrate Proteins / metabolism*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Maze Learning / drug effects
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Memory Disorders / physiopathology
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Memory Disorders / prevention & control*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptide Fragments / metabolism
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Phosphorylation / drug effects
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Presenilin-1 / genetics
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Presenilin-1 / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Serine / metabolism
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Signal Transduction / drug effects*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Insulin Receptor Substrate Proteins
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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Tumor Necrosis Factor-alpha
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amyloid beta-protein (1-42)
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Serine
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Catechin
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epigallocatechin gallate
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3