Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

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

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

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

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.
Literature
1.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.PubMedCrossRef
2.
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.PubMedCentralPubMedCrossRef
3.
4.
5.
Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A. 1997;94:4312–7.PubMedCentralPubMedCrossRef
6.
7.
Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways. Circ Res. 2011;108:985–95.PubMedCentralPubMedCrossRef
8.
Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT. PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci. 2012;32:17321–31.PubMedCrossRef
9.
Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA, Holtzman DM, et al. Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci. 2011;31:7049–59.PubMedCrossRef
10.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–6.PubMedCentralPubMedCrossRef
11.
Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci. 2012;32:10117–28.PubMedCentralPubMedCrossRef
12.
Bishop-Bailey D, Bystrom J. Emerging roles of peroxisome proliferator-activated receptor-beta/delta in inflammation. Pharmacol Ther. 2009;124:141–50.PubMedCrossRef
13.
Martin HL, Mounsey RB, Sathe K, Mustafa S, Nelson MC, Evans RM, et al. A peroxisome proliferator-activated receptor-delta agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience. 2013;240:191–203.PubMedCentralPubMedCrossRef
14.
Iwashita A, Muramatsu Y, Yamazaki T, Muramoto M, Kita Y, Yamazaki S, et al. Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. J Pharmacol Exp Ther. 2007;320:1087–96.PubMedCrossRef
15.
Yin KJ, Deng Z, Hamblin M, Xiang Y, Huang H, Zhang J, et al. Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci. 2010;30:6398–408.PubMedCentralPubMedCrossRef
16.
Paterniti I, Esposito E, Mazzon E, Galuppo M, Di Paola R, Bramanti P, et al. Evidence for the role of peroxisome proliferator-activated receptor-beta/delta in the development of spinal cord injury. J Pharmacol Exp Ther. 2010;333:465–77.PubMedCrossRef
17.
de la Monte SM, Tong M, Lester-Coll N, Plater Jr M, Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease. J Alzheimers Dis. 2006;10:89–109.PubMed
18.
Kalinin S, Richardson JC, Feinstein DL. A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res. 2009;6:431–7.PubMedCrossRef
19.
Liddell JR, Obando D, Liu J, Ganio G, Volitakis I, Mok SS, et al. Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: implications for Parkinson disease. Free Radic Biol Med. 2013;60:147–56.PubMedCrossRef
20.
Gresa-Arribas N, Vieitez C, Dentesano G, Serratosa J, Saura J, Sola C. Modelling neuroinflammation in vitro: a tool to test the potential neuroprotective effect of anti-inflammatory agents. PLoS One. 2012;7:e45227.PubMedCentralPubMedCrossRef
21.
22.
Heraud C, Goufak D, Ando K, Leroy K, Suain V, Yilmaz Z, et al. Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice. Neurobiol Dis. 2014;62:100–12.PubMedCrossRef
23.
Devi L, Ohno M. Phospho-eIF2alpha level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS One. 2010;5:e12974.PubMedCentralPubMedCrossRef
24.
Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging. 2012;33:196. e29-196.e40.PubMed
25.
Moon M, Hong HS, Nam DW, Baik SH, Song H, Kook SY, et al. Intracellular amyloid-beta accumulation in calcium-binding protein-deficient neurons leads to amyloid-beta plaque formation in animal model of Alzheimer’s disease. J Alzheimers Dis. 2012;29:615–28.PubMed
26.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40.PubMedCrossRef
27.
Lee CY, Tse W, Smith JD, Landreth GE. Apolipoprotein E promotes beta-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem. 2012;287:2032–44.PubMedCentralPubMedCrossRef
28.
Oliver Jr WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001;98:5306–11.PubMedCentralPubMedCrossRef
29.
Ogata M, Tsujita M, Hossain MA, Akita N, Gonzalez FJ, Staels B, et al. On the mechanism for PPAR agonists to enhance ABCA1 gene expression. Atherosclerosis. 2009;205:413–9.PubMedCentralPubMedCrossRef
30.
Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res. 2014;79:1–12.PubMedCrossRef
31.
Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O. CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One. 2012;7:e30525.PubMedCentralPubMedCrossRef
32.
Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, et al. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol. 2006;63:538–43.PubMedCrossRef
33.
Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol. 2009;19:392–8.PubMedCrossRef
34.
Xia MQ, Hyman BT. Chemokines/chemokine receptors in the central nervous system and Alzheimer’s disease. J Neurovirol. 1999;5:32–41.PubMedCrossRef
35.
Kiyota T, Yamamoto M, Schroder B, Jacobsen MT, Swan RJ, Lambert MP, et al. AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice. Mol Ther. 2009;17:803–9.PubMedCentralPubMedCrossRef
36.
Handattu SP, Garber DW, Monroe CE, van Groen T, Kadish I, Nayyar G, et al. Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2009;34:525–34.PubMedCrossRef
37.
Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177:2549–62.PubMedCentralPubMedCrossRef
38.
Bakshi P, Margenthaler E, Reed J, Crawford F, Mullan M. Depletion of CXCR2 inhibits gamma-secretase activity and amyloid-beta production in a murine model of Alzheimer’s disease. Cytokine. 2011;53:163–9.PubMedCrossRef
39.
Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol. 1999;154:927–36.PubMedCentralPubMedCrossRef
40.
Bergamaschini L, Canziani S, Bottasso B, Cugno M, Braidotti P, Agostoni A. Alzheimer’s beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner. Clin Exp Immunol. 1999;115:526–33.PubMedCentralPubMedCrossRef
41.
Jiang H, Burdick D, Glabe CG, Cotman CW, Tenner AJ. beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J Immunol. 1994;152:5050–9.PubMed
42.
Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, et al. Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1992;89:10016–20.PubMedCentralPubMedCrossRef
43.
44.
Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112:733–43.PubMedCentralPubMedCrossRef
45.
Fu H, Liu B, Frost JL, Hong S, Jin M, Ostaszewski B, et al. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Abeta by microglia. Glia. 2012;60:993–1003.PubMedCentralPubMedCrossRef
46.
Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008;28:6333–41.PubMedCentralPubMedCrossRef
47.
Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2004;24:6457–65.PubMedCrossRef
48.
Crehan H, Hardy J, Pocock J. Blockage of CR1 prevents activation of rodent microglia. Neurobiol Dis. 2013;54:139–49.PubMedCrossRef
49.
Farber K, Cheung G, Mitchell D, Wallis R, Weihe E, Schwaeble W, et al. C1q, the recognition subcomponent of the classical pathway of complement, drives microglial activation. J Neurosci Res. 2009;87:644–52.PubMedCentralPubMedCrossRef
50.
Cannon JR, Greenamyre JT. NeuN is not a reliable marker of dopamine neurons in rat substantia nigra. Neurosci Lett. 2009;464:14–7.PubMedCrossRef
51.
Polak PE, Kalinin S, Dello Russo C, Gavrilyuk V, Sharp A, Peters JM, et al. Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005;168:65–75.PubMedCrossRef
52.
Jin H, Ham SA, Kim MY, Woo IS, Kang ES, Hwang JS, et al. Activation of peroxisome proliferator-activated receptor-delta attenuates glutamate-induced neurotoxicity in HT22 mouse hippocampal cells. J Neurosci Res. 2012;90:1646–53.PubMedCrossRef
53.
Smith SA, Monteith GR, Robinson JA, Venkata NG, May FJ, Roberts-Thomson SJ. Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons. J Neurosci Res. 2004;77:240–9.PubMedCrossRef
Metadata
Title
Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation
Authors
Tarja Malm
Monica Mariani
Lauren J Donovan
Lee Neilson
Gary E Landreth
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-014-0229-9

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue

Review

‘Medusa head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 2: Anti-PKC-gamma, anti-GluR-delta2, anti-Ca/ARHGAP26 and anti-VGCC

Research

Cu(II) enhances the effect of Alzheimer’s amyloid-β peptide on microglial activation

Research

CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system

Research

Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes

Research

Amelioration of Japanese encephalitis by blockage of 4-1BB signaling is coupled to divergent enhancement of type I/II IFN responses and Ly-6Chi monocyte differentiation

Research

Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension