Abstract
Targeting the common molecular mechanism of type 2 diabetes mellitus and Alzheimer's disease (AD), including dysregulation of glucose metabolism, insulin resistance, and neuroinflammation, might be an efficient treatment strategy for AD. Previous studies have shown that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous PPARγ agonist, has anti-inflammatory, insulin sensitizing and anti-diabetic effects. However, whether 15d-PGJ2 has beneficial effects on AD remains to be elucidated. In the present study, we found that intranasal administration of 15d-PGJ2 (300 ng/30 μL/day) for 3 months significantly inhibited Aβ plaques, suppressed neuroinflammation, and attenuated cognitive deficits in APP/PS1 transgenic mice. Interestingly, 15d-PGJ2 treatment could increase brain glucose uptake, as detected by 18F-FDG microPET imaging, and co-localization of GLUT4 and NeuN in the hippocampus of APP/PS1 mice. Furthermore, 15d-PGJ2 markedly increased the expression of PPARγ and PGC-1α, upregulated GLUT4, and decreased the phosphorylation of IRS-1 (Ser616) in the hippocampus of APP/PS1 mice. Importantly, co-administration of a PPARγ antagonist GW9662 abrogated these protective effects of 15d-PGJ2. Collectively, intranasal 15d-PGJ2 conferred protective effects against AD by activating PPARγ-dependent PGC-1α/GLUT4 signalling. The PPARγ agonist 15d-PGJ2 might be a potential therapeutic drug for AD.
Keywords:
APP/PS1 transgenic mice; Insulin resistance; Neuroinflammation; PPARγ; microPET.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intranasal
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Amyloid beta-Peptides / drug effects
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Anilides / pharmacology
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Animals
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Behavior, Animal / drug effects
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Brain / diagnostic imaging
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Brain / drug effects*
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Brain / metabolism
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Cytokines / drug effects
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Cytokines / metabolism
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Fluorodeoxyglucose F18
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Glucose / metabolism*
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Glucose Transporter Type 4 / drug effects
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Glucose Transporter Type 4 / metabolism
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Hippocampus / drug effects
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Hippocampus / metabolism
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Immunologic Factors / pharmacology*
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Mice
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Mice, Transgenic
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Morris Water Maze Test
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Neurons / drug effects*
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Neurons / metabolism
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PPAR gamma / antagonists & inhibitors
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PPAR gamma / drug effects*
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PPAR gamma / metabolism
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Peptide Fragments / drug effects
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Peptide Fragments / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / drug effects
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
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Positron-Emission Tomography
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Presenilin-1 / genetics
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / pharmacology
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Radiopharmaceuticals
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Signal Transduction
Substances
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15-deoxy-delta(12,14)-prostaglandin J2
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2-chloro-5-nitrobenzanilide
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APP protein, human
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Anilides
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Cytokines
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Glucose Transporter Type 4
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Immunologic Factors
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PPAR gamma
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PSEN1 protein, human
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Peptide Fragments
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Presenilin-1
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Radiopharmaceuticals
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Slc2a4 protein, mouse
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Fluorodeoxyglucose F18
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Glucose
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Prostaglandin D2