Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation

Malm, Tarja; Mariani, Monica; Donovan, Lauren J; Neilson, Lee; Landreth, Gary E

doi:10.1186/s12974-014-0229-9

Cited by 77Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsPeroxisome Proliferator-Activated Receptors

Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation

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Malm, Tarja, Mariani, Monica, Donovan, Lauren J, Neilson, Lee, Landreth, Gary E·2015·Journal of Neuroinflammation

DOI 10.1186/s12974-014-0229-9PMC PMC4310027

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Abstract

BACKGROUND: Alzheimer's disease (AD) is a multifactorial disorder associated with the accumulation of soluble forms of beta-amyloid (Aβ) and its subsequent deposition into plaques. One of the major contributors to neuronal death is chronic and uncontrolled inflammatory activation of microglial cells around the plaques and their secretion of neurotoxic molecules. A shift in microglial activation towards a phagocytic phenotype has been proposed to confer benefit in models of AD. Peroxisome proliferator activator receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory activation properties and PPARδ agonism leads to reduction in brain Aβ levels in 5XFAD mice. This study was carried out to elucidate the involvement of microglial activation in the PPARδ-mediated reduction of Aβ burden and subsequent outcome to neuronal survival in a 5XFAD mouse model of AD. METHODS: 5XFAD mice were orally treated with the PPARδ agonist GW0742 for 2 weeks. The brain Aβ load, glial activation, and neuronal survival were assessed by immunohistochemistry and quantitative PCR. In addition, the ability of GW0742 to prevent direct neuronal death as well as inflammation-induced neuron death was analyzed in vitro. RESULTS: Our results show for the first time that a short treatment period of 5XFAD mice was effective in reducing the parenchymal Aβ load without affecting the levels of intraneuronal Aβ. This was concomitant with a decrease in overall microglial activation and reduction in proinflammatory mediators. Instead, microglial immunoreactivity around Aβ deposits was increased. Importantly, the reduction in the proinflammatory milieu elicited by GW0742 treatment resulted in attenuation of neuronal loss in vivo in the subiculum of 5XFAD mice. In addition, whereas GW0742 failed to protect primary neurons against glutamate-induced cell death, it prevented inflammation-induced neuronal death in microglia-neuron co-cultures in vitro. CONCLUSIONS: This study demonstrates that GW0742 treatment has a prominent anti-inflammatory effect in 5XFAD mice and suggests that PPARδ agonists may have therapeutic utility in treating AD.

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In murine models of Alzheimer's disease and neuroinflammation, studies of the effects of nuclear receptor agonists have been focused principally on their actions in astrocytes and microglia.
“In murine models of AD and neuroinflammation, studies of the effects of nuclear receptor agonists have been focused principally on their actions in astrocytes and microglia5678.”
From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [7]
PPARδ agonist GW0742 did not reduce intraneuronal 6E10 immunoreactivity in layer V neurons.
“In contrast, we have recently reported that PPARδ agonist GW0742 did not reduce intraneuronal 6E10 immunoreactivity in layer V neurons7.”
From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [7]

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Additional file 2 of Intracerebral overexpression of miR-669c is protective in mouse ischemic stroke model by targeting MyD88 and inducing alternative microglial/macrophage activation
Kołosowska, N., Gotkiewicz, M., Dhungana, H., Giudice, L., Giugno, R., Box, D., Huuskonen, M. T., Korhonen, P., Scoyni, F., Kanninen, K. M., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12519434
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Additional file 1 of Intracerebral overexpression of miR-669c is protective in mouse ischemic stroke model by targeting MyD88 and inducing alternative microglial/macrophage activation
Kołosowska, N., Gotkiewicz, M., Dhungana, H., Giudice, L., Giugno, R., Box, D., Huuskonen, M. T., Korhonen, P., Scoyni, F., Kanninen, K. M., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12519425
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Authors: Malm, T., Mariani, M., Donovan, L. J., Neilson, L., & Landreth, G. E.
Affiliations: University of Eastern Finland (FI)
Case Western Reserve University (US)
Corresponding author: Landreth, Gary E
ORCID: Malm, Tarja
Donovan, Lauren J
Neilson, Lee
Landreth, Gary E
Venue: Journal of Neuroinflammation
Publisher: Springer Science and Business Media LLC
Published: 2015-01-16
Volume: 12
Issue: 1
Pages: 7-7
ISSN: 1742-2094 (ISSN-L)
DOI: 10.1186/s12974-014-0229-9
PMC: PMC4310027
OpenAlex: W2119098046
Cited by: 77
References: 54
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 9 · 2022: 6 · 2021: 6 · 2020: 10 · 2019: 9 · 2018: 12 · 2017: 7 · 2016: 8 · 2015: 4
FWCI: 7.62
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Journal of Neuroinflammation (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: GlaxoSmithKline
BrightFocus Foundation
Academy of Finland
Suomen Kulttuurirahasto
National Institute on Aging (R01AG043522, RF1AG050597)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: PPARδ, Alzheimer's disease, neuroprotection, microglial activation, neuroinflammation, amyloid-beta, 5xFAD mice, GW0742, PPARδ agonist, anti-inflammatory therapy, neuronal cell death, glutamate-induced neuronal death, subiculum, microglia-neuron co-culture
MeSH terms: Alzheimer Disease, Animals, Animals, Newborn, Anti-Inflammatory Agents, Calcium-Binding Proteins, Cells, Cultured, Complement C3, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Inflammation, Male, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Phenols, Phosphopyruvate Hydratase, Sulfhydryl Compounds, Thiazoles, Cell Adhesion Molecules, Complement C1q, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, PPAR delta, Mice

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Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation

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