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CNS Drugs

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01-01-2008 | Leading Article

The Role of Peroxisome Proliferator-Activated Receptor-γ PPARγ) in Alzheimer’s Disease

Therapeutic Implications

Authors: Qingguang Jiang, Michael Heneka, Dr Gary E. Landreth

Published in: CNS Drugs | Issue 1/2008

Abstract

Alzheimer’s disease is a complex neurodegenerative disorder, with aging, genetic and environmental factors contributing to its development and progression. The complexity of Alzheimer’s disease presents substantial challenges for the development of new therapeutic agents. Alzheimer’s disease is typified by pathological depositions of β-amyloid peptides and neurofibrillary tangles within the diseased brain. It has also been demonstrated to be associated with a significant microglia-mediated inflammatory component, dysregulated lipid homeostasis and regional deficits in glucose metabolism within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism, and is found in elevated levels in the brains of individuals with Alzheimer’s disease. A recently appreciated physiological function of this type of receptor is its ability to modulate inflammatory responses. In animal models of Alzheimer’s disease, PPARγ agonist treatment results in the reduction of amyloid plaque burden, reduced inflammation and reversal of disease-related behavioural impairment. In a recent phase II clinical trial, the use of the PPARγ agonist rosiglitazone was associated with improved cognition and memory in patients with mild to moderate Alzheimer’s disease. Thus, PPARγ may act to modulate multiple pathophysiological mechanisms that contribute to Alzheimer’s disease, and represents an attractive therapeutic target for the treatment of the disease.

Blennow K, De Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006; 368: 387–403PubMedCrossRef

Kersten S, Desvergne B, Wahli W. Roles of PPARs in healthand disease. Nature 2000; 405(6785): 421–4PubMedCrossRef

Sundararajan S, Jiang Q, Heneka M, et al. PPARγ as a therapeutic target in central nervous system diseases. Neurochem Int 2006; 49(2): 136–44PubMedCrossRef

Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005; 120(4): 545–55PubMedCrossRef

Price DL, Tanzi RE, Borchelt DR, et al. Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 1998; 32: 461–93PubMedCrossRef

Puglielli L, Tanzi R, Kovacs D. Alzheimer’s disease: the cholesterol connection. Nat Neurosci 2003; 6(4): 345–51PubMedCrossRef

Wolozin B. Cholesterol and the biology of Alzheimer’s disease. Neuron 2004; 41(1): 7–10PubMedCrossRef

Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993; 90(5): 1977–81PubMedCrossRef

Hansen LA, Galasko D, Samuel W, et al. Apolipoprotein-E epsilon-4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer’s disease. Neurosci Lett 1994; 182(1): 63–5PubMedCrossRef

10.

Roses AD, Saunders AM. APOE is a major susceptibility gene for Alzheimer’s disease. Curr Opin Biotechnol 1994; 5(6): 663–7PubMedCrossRef

11.

Roses AD, Saunders AM, Corder H, et al. Influence of the susceptibility genes apolipoprotein E-epsilon 4 and apolipoprotein E-epsilon 2 on the rate of disease expressivity of late-onset Alzheimer’s disease. Arzneimittelforschung 1995; 45(3A): 413–7PubMed

12.

Rogers J, Webster S, Lue LF, et al. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 1996; 17(5): 681–6PubMedCrossRef

13.

Aisen PS. Inflammation and Alzheimer’s disease: mechanisms and therapeutic strategies. Gerontology 1997; 43(1-2): 143–9PubMedCrossRef

14.

Bamberger ME, Landreth GE. Inflammation, apoptosis, and Alzheimer’s disease. Neuroscientist 2002; 8(3): 276–83PubMed

15.

Rogers J, Shen Y. A perspective on inflammation in Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 132–5PubMedCrossRef

16.

Brown III J, Theisler C, Silberman S, et al. Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J Biol Chem 2004; 279(33): 34674–81PubMedCrossRef

17.

Bookout AL, Jeong Y, Downes M, et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006; 126(4): 789–99PubMedCrossRef

18.

Victor NA, Wanderi EW, Gamboa J, et al. Altered PPARγ expression and activation after transient focal ischemia in rats. Eur J Neurosci 2006; 24(6): 1653–63PubMedCrossRef

19.

Kitamura Y, Shimohama S, Koike H, et al. Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer’s disease brains. Biochem Biophys Res Commun 1999; 254(3): 582–6PubMedCrossRef

20.

de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 2006; 9(2): 167–81PubMed

21.

Yan Q, Zhang J, Liu H, et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci 2003; 23(20): 7504–9PubMed

22.

Heneka M, Sastre M, Dumitrescu-Ozimek, et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Abetal-42 levels in APPV717I transgenic mice. Brain 2005; 128 (Pt 6): 1442–53PubMedCrossRef

23.

in’t Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345(21): 1515–21CrossRef

24.

Lim GP, Yang F, Chu T, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000; 20(15): 5709–14PubMed

25.

Lim GP, Yang F, Chu T, et al. Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging 2001; 22(6): 983–91PubMedCrossRef

26.

Lehmann JM, Lenhard JM, Oliver B, et al. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997; 272: 3406–10PubMedCrossRef

27.

Maeshiba Y, Kiyota Y, Yamashita K, et al. Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 1997; 47(1): 29–35 29.PubMed

28.

Eriksen J, Sagi S, Smith T, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003; 112(3): 440–9PubMed

29.

Weggen S, Eriksen JL, Das, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414(6860): 212–6PubMedCrossRef

30.

Weggen S, Eriksen J, Sagi S, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem 2003; 278(34): 31831–7PubMedCrossRef

31.

Morihara T, Teter B, Yang F, et al. Ibuprofen suppresses interleukin-lbeta induction of pro-amyloidogenic alphal-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer’s models. Neuropsychopharmacology 2005; 30(6): 1111–20PubMedCrossRef

32.

Lanz TA, Fici GJ, Merchant KM. Lack of specific amyloid-beta(l–42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures. J Pharmacol Exp Ther 2005; 312(1): 399–406PubMedCrossRef

33.

Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 2001; 15(12): 2057–72PubMedCrossRef

34.

Aisen PS. Anti-inflammatory agents in Alzheimer’s Disease. Curr Neurol Neurosci Rep 2002; 2(5): 405–9PubMedCrossRef

35.

Pedersen W, McMillan P, Kulstad J, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006; 199(2): 265–73PubMedCrossRef

36.

Vekrellis K, Ye Z, Qiu WQ, et al. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci 2000; 20(5): 1657–65PubMed

37.

Strum JC, Shehee R, Virley D, et al. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 2007; 11: 45–51PubMed

38.

Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005; 13(11): 950–8PubMed

39.

Geldmacher D, Fritsch T, McClendon M, et al. A pilot study of pioglitazone in Alzheimer disease. International Conference on Alzheimer’s disease and related dementias; 2006 Jul 15–20; Madrid

40.

Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-tomoderate Alzheimer’s disease. Pharmacogenomics J 2006; 6(4): 246–54PubMed

41.

Kuusisto J, Koivisto K, Mykkanen L, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 1997; 315(7115): 1045–9PubMedCrossRef

42.

Craft S, Asthana S, Schellenberg G, et al. Insulin metabolism in Alzheimer’s disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology 1999; 70(2): 146–52PubMedCrossRef

43.

Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci 2000; 903: 222–8]PubMedCrossRef

44.

ClinicalTrials.gov, a service of the US National Institutes of Health [online]. Available from URL: http://www.ClinicalTrials.gov [Accessed 2007 Nov 19]

45.

Pfutzner A, Weber MM, Forst T. Pioglitazone: update on an oral antidiabetic drug with antiatherosclerotic effects. Expert Opin Pharmacother 2007; 8: 1985–98PubMedCrossRef

46.

Nissen SE, Wolski K. Effect of rosiglitazone on risk of myocardial infarction and death from cardiovcascular causes. N Engl J Med 2007; 356: 2457–71PubMedCrossRef

47.

Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298: 1180–8PubMedCrossRef

48.

Waugh J, Keating GM, Plosker GL, et al. Pioglitazone: a review of its use in type 2 diabetes mellitus. Drugs 2006; 66(1): 85–109PubMedCrossRef

49.

Castrillo A, Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu Rev Cell Dev Biol 2004; 20: 455–80PubMedCrossRef

50.

Chawla A, Boisvert WA, Lee CH, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 2001; 7(1): 161–71PubMedCrossRef

51.

Kliewer SA, Lehmann JM, Willson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science 1999; 284(5415): 757–60PubMedCrossRef

52.

Lehrke M, Lazar M. The many faces of PPARγ. Cell 2005; 123(6): 993–9PubMedCrossRef

53.

Picard F, Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 2002; 22: 167–97PubMedCrossRef

54.

Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2(10): 748–59PubMedCrossRef

55.

Fajas L, Fruchart JC, Auwerx J. Transcriptional control of adipogenesis. Curr Opin Cell Biol 1998; 10(2): 165–73PubMedCrossRef

56.

Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409–35PubMedCrossRef

57.

Aranda A, Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev 2001; 81(3): 1269–304PubMed

58.

Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000; 14(2): 121–41PubMed

59.

Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 2006; 6(1): 44–55PubMedCrossRef

60.

Ogawa S, Lozach J, Benner C, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 2005; 122(5): 707–21PubMedCrossRef

61.

Chung SW, Kang BY, Kim SH, et al. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 2000; 275(42): 32681–7PubMedCrossRef

62.

Chen F, Wang M, O’Connor JP, et al. Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappabeta. J Cell Biochem 2003; 90(4): 732–44PubMedCrossRef

63.

Subbaramaiah K, Lin DT, Hart JC, et al. Peroxisome proliferator-activated receptor gamma ligands suppress the transcrip-tional activation of cyclooxygenase-2: evidence for involvement of activator protein-1 and CREB-binding protein/p300. J Biol Chem 2001; 276(15): 12440–8PubMedCrossRef

64.

Li M, Pascual G, Glass CK. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 2000; 20(13): 4699–707PubMedCrossRef

65.

Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 2005; 437(7059): 759–63PubMedCrossRef

66.

Colangelo V, Schurr J, Ball MJ, et al. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 2002; 70(3): 462–73PubMedCrossRef

67.

Owens T, Wekerle H, Antel J. Genetic models for CNS inflammation. Nat Med 2001; 7(2): 161–6PubMedCrossRef

68.

McGeer PL, McGeer EG. Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 2004; 1035: 104–16PubMedCrossRef

69.

Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 2005; 18(3): 315–21PubMedCrossRef

70.

Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308(5726): 1314–8PubMedCrossRef

71.

Sly LM, Krzesicki RF, Brashler JR, et al. Endogenous brain cytokine mRNA and inflammatory responses to lipo-polysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer’s disease. Brain Res Bull 2001; 56(6): 581–8PubMedCrossRef

72.

Lue LF, Walker DG, Rogers J. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures. Neurobiol Aging 2001; 22(6): 945–56PubMedCrossRef

73.

German DC, Eisch AJ. Mouse models of Alzheimer’s disease: insight into treatment. Rev Neurosci 2004; 15(5): 353–69PubMedCrossRef

74.

Klegeris A, McGeer PL. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr Alzheimer Res 2005; 2(3): 355–65PubMedCrossRef

75.

Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21(3): 383–421PubMedCrossRef

76.

Qiao X, Cummins DJ, Paul SM. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 2001; 14(3): 474–82PubMedCrossRef

77.

Sheng JG, Bora SH, Xu G, et al. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APP-swe transgenic mice. Neurobiol Dis 2003; 14(1): 133–45PubMedCrossRef

78.

Lim GP, Chu T, Yang F, et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001; 21(21): 8370–7PubMed

79.

Harris-White ME, Chu T, Balverde Z, et al. Effects of transforming growth factor-beta (isoforms 1–3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures. J Neurosci 1998; 18(24): 10366–74PubMed

80.

Herber DL, Roth LM, Wilson D, et al. Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 2004; 190(1): 245–53PubMedCrossRef

81.

Majumdar A, Cruz D, Asamoah N, et al. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 2007; 18(4): 1490–6PubMedCrossRef

82.

Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12(9): 1005–15PubMed

83.

Blasko I, Veerhuis R, Stampfer-Kountchev M, et al. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol Dis 2000; 7 (6 Pt B): 682–9PubMedCrossRef

84.

Blasko I, Apochal A, Boeck G, et al. Ibuprofen decreases cytokine-induced amyloid beta production in neuronal cells. Neurobiol Dis 2001; 8(6): 1094–101PubMedCrossRef

85.

Grilli M, Ribola M, Alberici A, et al. Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. J Biol Chem 1995; 270(45): 26774–7PubMedCrossRef

86.

Grilli M, Goffi F, Memo M, et al. Interleukin-lbeta and glutamate activate the NF-kappaB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures. J Biol Chem 1996; 271(25): 15002–7PubMedCrossRef

87.

Rogers JT, Leiter LM, McPhee J, et al. Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences. J Biol Chem 1999; 274(10): 6421–31PubMedCrossRef

88.

Sastre M, Dewachter I, Landreth GE, et al. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 2003; 23(30): 9796–804PubMed

89.

Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A 2006; 103(2): 443–8PubMedCrossRef

90.

Dash PK, Moore AN. Enhanced processing of APP induced by IL-1 beta can be reduced by indomethacin and nordihydroguaiaretic acid. Biochem Biophys Res Commun 1995; 208(2): 542–8PubMedCrossRef

91.

Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 2005; 25(36): 8240–9PubMedCrossRef

92.

Craft S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiology of Aging 2005; 26Suppl. 1: 65–9PubMedCrossRef

93.

Watson G, Craft S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 2004; 490(1-3): 97–113PubMedCrossRef

94.

Watson GS, Craft S. The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 2003; 17(1): 27–45PubMedCrossRef

95.

Luchsinger JA, Tang MX, Stern Y, et al. Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001; 154(7): 635–41PubMedCrossRef

96.

Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes 2002; 51(4): 1256–62PubMedCrossRef

97.

Craft S, Dagogo-Jack SE, Wiethop BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neurosci 1993; 107(6): 926–40PubMedCrossRef

98.

Reiman EM, Caselli RJ, Chen K, et al. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proc Natl Acad Sci U S A 2001; 98(6): 3334–9PubMedCrossRef

99.

Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 2000; 97(11): 6037–42PubMedCrossRef

100.

Trivedi MA, Schmitz TW, Ries ML, et al. Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer’s disease: a cross-sectional study. BMC Med 2006; 4: 1PubMedCrossRef

101.

Mosconi L, Tsui WH, De Santi S, et al. Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 2005; 64(11): 1860–7PubMedCrossRef

102.

Nestor PJ, Fryer TD, Smielewski P, et al. Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 2003; 54(3): 343–51PubMedCrossRef

103.

De Santi S, de Leon MJ, Rusinek H, et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging 2001; 22(4): 529–39PubMedCrossRef

104.

Ibanez V, Pietrini P, Alexander GE, et al. Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology 1998; 50(6): 1585–93PubMedCrossRef

105.

Small GW, Mazziotta JC, Collins MT, et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995; 273(12): 942–7PubMedCrossRef

106.

Kulstad J, Green P, Cook D, et al. Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease. Neurology 2006; 66: 1506–10PubMedCrossRef

107.

Gasparini L, Gouras GK, Wang R, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001; 21(8): 2561–70PubMed

108.

Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998; 273(49): 32730–8PubMedCrossRef

109.

Sjoholm A, Nystrom T. Endothelial inflammation in insulin resistance. Lancet 2005; 365(9459): 610–2PubMed

110.

Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med 2004; 117(2): 109–17PubMedCrossRef

111.

Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med 2000; 343(7): 450–6PubMedCrossRef

112.

Feinstein D, Spagnolo A, Akar C, et al. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochem Pharmacol 2005; 70(2): 177–88PubMedCrossRef

113.

d’Abramo C, Massone S, Zingg JM, et al. Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. Biochem J 2005; 391 (Pt 3): 693–8PubMedCrossRef

114.

Camacho IE, Serneels L, Spittaels K, et al. Peroxisome proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 2004; 24(48): 10908–17PubMedCrossRef

115.

Llaverias G, Rebollo A, Pou J, et al. Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes. Biochem Pharmacol 2006; 71(5): 605–14PubMedCrossRef

116.

Calkin AC, Forbes JM, Smith CM, et al. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol 2005; 25(9): 1903–9PubMedCrossRef

117.

Yue L, Rasouli N, Ranganathan G, et al. Divergent effects of peroxisome proliferator-activated receptor gamma agonists and tumor necrosis factor alpha on adipocyte ApoE expression. J Biol Chem 2004; 279(46): 47626–32PubMedCrossRef

118.

Seo JB, Moon HM, Kim WS, et al. Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol 2004; 24(8): 3430–44PubMedCrossRef

119.

Piraino G, Cook JA, O’Connor M, et al. Synergistic effect of peroxisome proliferator activated receptor-gamma and liver X receptor-alpha in the regulation of inflammation in macrophages. Shock 2006; 26(2): 146–53PubMedCrossRef

120.

Katzov H, Chalmers K, Palmgren J, et al. Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism. Hum Mutat 2004; 23(4): 358–67PubMedCrossRef

121.

Li Y, Tacey K, Doil L, et al. Association of ABCA1 with lateonset Alzheimer’s disease is not observed in a case-control study. Neurosci Lett 2004; 366(3): 268–71PubMedCrossRef

122.

Adighibe O, Arepalli S, Duckworth J, et al. Genetic variability at the LXR gene (NR1H2) may contribute to the risk of Alzheimer’s disease. Neurobiol Aging 2006; 27(10): 1431–4PubMedCrossRef

123.

Wolozin B. Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol 2003; 60(1): 16–8PubMedCrossRef

124.

Grainger DJ, Reckless J, McKilligin E. Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice. J Immunol 2004; 173(10): 6366–75PubMed

125.

Ali K, Middleton M, Pure E, et al. Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ Res 2005; 97(9): 922–7PubMedCrossRef

126.

Wuttge DM, Sirsjo A, Eriksson P, et al. Gene expression in atherosclerotic lesion of ApoE deficient mice. Mol Med 2001; 7(6): 383–92PubMed

127.

Berbee JF, Havekes LM, Rensen PC. Apolipoproteins modulate the inflammatory response to lipopolysaccharide. J Endotoxin Res 2005; 11(2): 97–103PubMed

128.

Phillips JW, Barringhaus KG, Sanders JM, et al. Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes. Circulation 2003; 108(16): 1994–9PubMedCrossRef

129.

Chen Z, Ishibashi S, Perrey S, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 2001; 21(3): 372–7PubMedCrossRef

130.

Tordjman K, Bernal-Mizrachi C, Zemany L, et al. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J Clin Invest 2001; 107(8): 1025–34PubMedCrossRef

131.

Feingold KR, Hardardottir I, Memon R, et al. Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters. J Lipid Res 1993; 34(12): 2147–58PubMed

132.

Wang Y, Moser AH, Shigenaga JK, et al. Downregulation of liver X receptor-alpha in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines. J Lipid Res 2005; 46(11): 2377–87PubMedCrossRef

133.

Ripolles Piquer B, Nazih H, Neunlist M, et al. Effect of LPS on basal and induced apo E secretion by 25-OH chol and 9cRA in differentiated CaCo-2. J Cell Biochem 2004; 91(4): 786–95PubMedCrossRef

134.

Joseph SB, Castrillo A, Laffitte BA, et al. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003; 9(2): 213–9PubMedCrossRef

135.

Joseph SB, McKilligin E, Pei L, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A 2002; 99(11): 7604–9PubMedCrossRef

136.

Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 2006; 116(3): 607–14PubMedCrossRef

137.

Wellington CL. Cholesterol at the crossroads: Alzheimer’s disease and lipid metabolism. Clin Genet 2004; 66(1): 1–16PubMedCrossRef

138.

Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004; 24(5): 806–15PubMedCrossRef

139.

Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003; 28(6): 809–22PubMedCrossRef

140.

Rasgon N, Jarvik L. Insulin resistance, affective disorders, and Alzheimer’s disease: review and hypothesis. J Gerontol A Biol Sci Med Sci 2004; 59(2): 178–83, discussion 184-92PubMedCrossRef

141.

Pedersen WA, Flynn ER. Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 2004; 17(3): 500–6PubMedCrossRef

142.

Luchsinger JA, Mayeux R. Cardiovascular risk factors and Alzheimer’s disease. Curr Atheroscler Rep 2004; 6(4): 261–6PubMedCrossRef

143.

de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis 2005; 7(1): 45–61PubMed

144.

Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med 2004; 82(8): 510–29PubMedCrossRef

145.

Nicolls MR. The clinical and biological relationship between type II diabetes mellitus and Alzheimer’s disease. Curr Alzheimer Res 2004; 1(1): 47–54PubMedCrossRef

146.

Fishel MA, Watson GS, Montine TJ, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005; 62(10): 1539–44PubMedCrossRef

147.

Rasgon NL, Kenna HA. Insulin resistance in depressive disorders and Alzheimer’s disease: revisiting the missing link hypothesis. Neurobiol Aging 2005; 26Suppl. 1: 103–7PubMedCrossRef

148.

Biessels GJ, Kappelle LJ. Increased risk of Alzheimer’s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 2005; 33 (Pt 5): 1041–4PubMedCrossRef

149.

Watson G, Cholerton B, Reger M, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005; 13(11): 950–8PubMed

150.

Messier C, Teutenberg K. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer’s disease. Neural Plast 2005; 12(4): 311–28PubMedCrossRef

151.

Watson GS, Craft S. Insulin resistance, inflammation, and cognition in Alzheimer’s Disease: lessons for multiple sclerosis. J Neurol Sci 2006; 245(1-2): 21–33PubMedCrossRef

152.

Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry 2006; 11(8): 721–36PubMedCrossRef

153.

Hsueh W. Genetic discoveries as the basis of personalized therapy: rosiglitazone treatment of Alzheimer’s disease. Pharmacogenomics J 2006; 6(4): 222–4PubMedCrossRef

154.

Alarcon de la Lastra C, Sanchez-Fidalgo S, Villegas I, et al. New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists. Curr Pharm Des 2004; 10(28): 3505–24PubMedCrossRef

155.

Ho L, Qin W, Pompl PN, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. Faseb J 2004; 18(7): 902–4PubMed

156.

Kudo T, Imaizumi K, Tanimukai H, et al. Are cerebrovascular factors involved in Alzheimer’s disease? Neurobiol Aging 2000; 21(2): 215–24PubMedCrossRef

157.

Razay G, Wilcock GK. Hyperinsulinaemia and Alzheimer’s disease. Age Ageing 1994; 23(5): 396–9PubMedCrossRef

158.

Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116(7): 1793–801PubMedCrossRef

159.

Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004; 25(1): 4–7PubMedCrossRef

160.

Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol 2003; 92(4A): 18–26JCrossRef

161.

Dandona P, Aljada A. A rational approach to pathogenesis and treatment of type 2 diabetes mellitus, insulin resistance, inflammation, and atherosclerosis. Am J Cardiol 2002; 90(5A): 27–33GCrossRef

162.

Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11(2): 183–90PubMedCrossRef

163.

Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11(2): 191–8PubMedCrossRef

164.

Farris W, Leissring MA, Hemming ML, et al. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry 2005; 44(17): 6513–25PubMedCrossRef

165.

Farris W, Mansourian S, Leissring MA, et al. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol 2004; 164(4): 1425–34PubMedCrossRef

166.

Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 2003; 100(7): 4162–7PubMedCrossRef

Title: The Role of Peroxisome Proliferator-Activated Receptor-γ PPARγ) in Alzheimer’s Disease
Therapeutic Implications
Authors: Qingguang Jiang
Michael Heneka
Dr Gary E. Landreth
Publication date: 01-01-2008
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 1/2008
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200822010-00001

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

The Role of Peroxisome Proliferator-Activated Receptor-γ PPARγ) in Alzheimer’s Disease

Therapeutic Implications

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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