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PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease
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  • Review Article
  • Published: July 2008

PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease

  • Gary Landreth1,3,
  • Qingguang Jiang1,
  • Shweta Mandrekar1 &
  • …
  • Michael Heneka2 

Neurotherapeutics volume 5, pages 481–489 (2008)Cite this article

  • 1386 Accesses

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Summary

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARγ agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARy agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARγ represents an important new therapeutic target in treating AD.

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References

  1. Sundararajan S, Jiang Q, Heneka M, et al. PPARgamma as a therapeutic target in central nervous system diseases. Neurochem Int 2006;49: 136–144.

    CAS  PubMed  Google Scholar 

  2. Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006;6: 246.

    CAS  PubMed  Google Scholar 

  3. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000;405: 421–424.

    CAS  PubMed  Google Scholar 

  4. Bookout AL, Jeong Y, Downes M, et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006;126: 789–799.

    CAS  PubMed  Google Scholar 

  5. Lehrke M, Lazar M. The many faces of PPARgamma. Cell (Cambridge) 2005;123: 993–999.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Pedersen W, McMillan P, Kulstad J, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006;199: 265–273.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Glass CK. Going nuclear in metabolic and cardiovascular disease. Eur J Clin Invest 2006;116: 556–560.

    CAS  Google Scholar 

  10. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53: 409–435.

    CAS  PubMed  Google Scholar 

  11. Aranda A, Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev 2001;81: 1269–1304.

    CAS  PubMed  Google Scholar 

  12. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000;14: 121–141.

    CAS  PubMed  Google Scholar 

  13. Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002;2: 748–759.

    CAS  PubMed  Google Scholar 

  14. Subbaramaiah K, Lin DT, Hart JC, et al. Peroxisome Proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2: evidence for involvement of activator protein-1 and CREB-binding protein/p300. J Biol Chem 2001;276: 12440–12448.

    CAS  PubMed  Google Scholar 

  15. 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: 4699–4707.

    CAS  PubMed  Google Scholar 

  16. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 2005;437: 759–763.

    CAS  PubMed  Google Scholar 

  17. 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: 7504–7509.

    CAS  PubMed  Google Scholar 

  18. 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: 5709–5714.

    CAS  PubMed  Google Scholar 

  19. Heneka M, Sastre M, Dumitrescu-Ozimek L, et al. Acute treatment with the PPARg agonist pioglitazone and ibuprofen reduces glial inflammation and Abetal-42 levels in APPV717I transgenic mice. Brain 2005;128: 1442–1453.

    PubMed  Google Scholar 

  20. Pedersen WA, Flynn ER. Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 2004;17: 500–506.

    CAS  PubMed  Google Scholar 

  21. Andrews R, Walker B. Glucocorticoids and insulin resistance: old hormones, new targets. Clinical science (London, England: 1979) 1999;96: 513–523.

    CAS  Google Scholar 

  22. Andrews RC, Herlihy O, Livingstone DE, et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab 2002;87: 5587–5593.

    CAS  PubMed  Google Scholar 

  23. Pomara N, Greenberg WM, Branford MD, et al. Therapeutic implications of HPA axis abnormalities in Alzheimer’s disease: review and update. Psychopharmacol Bull 2003;37: 120–134.

    PubMed  Google Scholar 

  24. Morcos M, Fohr B, Tafel J, et al. Long-term treatment of central Cushing’s syndrome with rosiglitazone. Exp Clin Endocrinol Diabetes 2007;115: 292–297.

    CAS  PubMed  Google Scholar 

  25. Ambrosi B, Dall’Asta C, Cannavo S, et al. Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing’s disease. Eur J Endocrinol 2004;151: 173–178.

    CAS  PubMed  Google Scholar 

  26. Heaney AP, Fernando M, Yong WH, et al. Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 2002;8: 1281–1287.

    CAS  PubMed  Google Scholar 

  27. Catrina SB, Virtanen K, Hallsten K, et al. Effect of rosiglitazone on early-moming plasma cortisol levels. Neuro Endocrinol Lett 2005;26: 763–764; author reply 765.

    PubMed  Google Scholar 

  28. 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: 950–958.

    PubMed  Google Scholar 

  29. Geldmacher D, Fritsch T, McClendon M, et al. A pilot study of pioglitazone in Alzheimer Disease. Int Conf Alz Dis Rel. Dementias; Madrid, July, 2006.

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

    CAS  PubMed  Google Scholar 

  31. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356: 2457–2471.

    CAS  PubMed  Google Scholar 

  32. 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: 1180–1188.

    CAS  PubMed  Google Scholar 

  33. 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: 1045–1049.

    CAS  PubMed  Google Scholar 

  34. 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: 146–152.

    CAS  PubMed  Google Scholar 

  35. 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: 222–228.

    CAS  PubMed  Google Scholar 

  36. 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: 9796–9804.

    CAS  PubMed  Google Scholar 

  37. 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: 443–448.

    CAS  PubMed  Google Scholar 

  38. 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: 693–698.

    PubMed  Google Scholar 

  39. Camacho IE, Semeels L, Spittaels K, et al. Peroxisome proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 2004;24: 10908–10917.

    CAS  PubMed  Google Scholar 

  40. Mosconi L, Tsui WH, De Santi S, et al. Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 2005;64: 1860–1867.

    CAS  PubMed  Google Scholar 

  41. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci U S A 2004;101: 284–289.

    CAS  PubMed  Google Scholar 

  42. 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: 3334–3339.

    CAS  PubMed  Google Scholar 

  43. 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: 6037–6042.

    CAS  PubMed  Google Scholar 

  44. 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: 942–947.

    CAS  PubMed  Google Scholar 

  45. Reiman EM, Chen K, Alexander GE, et al. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A 2005;102: 8299–8302.

    CAS  PubMed  Google Scholar 

  46. 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: 450–456.

    CAS  PubMed  Google Scholar 

  47. Castellani R, Hirai K, Aliev G, et al. Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 2002;70: 357–360.

    CAS  PubMed  Google Scholar 

  48. Roses AD, Saunders AM, Huang Y, et al. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer’s disease). Pharmacogenomics J 2007;7: 10–28.

    CAS  PubMed  Google Scholar 

  49. Bogacka I, Xie H, Bray GA, et al. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005;54: 1392–1399.

    CAS  PubMed  Google Scholar 

  50. Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 2006;27: 728–735.

    CAS  PubMed  Google Scholar 

  51. Hondares E, Mora O, Yubero P, et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-lalpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 2006;147: 2829–2838.

    CAS  PubMed  Google Scholar 

  52. Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999;98: 115–124.

    CAS  PubMed  Google Scholar 

  53. Kelly LJ, Vicario PP, Thompson GM, et al. Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology 1998;139: 4920–4927.

    CAS  PubMed  Google Scholar 

  54. Puigserver P, Wu Z, Park CW, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92: 829–839.

    CAS  PubMed  Google Scholar 

  55. Houten SM, Auwerx J. PGC-lalpha: turbocharging mitochondria. Cell 2004;119: 5–7.

    CAS  PubMed  Google Scholar 

  56. Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are co-ordinately downregulated in human diabetes. Nat Genet 2003;34: 267–273.

    CAS  PubMed  Google Scholar 

  57. Feinstem DL, Spagnolo A, Akar C, et al. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochem Pharmacol 2005;70: 177–188.

    Google Scholar 

  58. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5: 64–74.

    PubMed  Google Scholar 

  59. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Archives of Neurology 2007;64: 93–96.

    PubMed  Google Scholar 

  60. Razay G, Wilcock GK. Hyperinsulinaemia and Alzheimer’s disease. Age Ageing 1994;23: 396–399.

    CAS  PubMed  Google Scholar 

  61. Craft S, Peskind E, Schwartz MW, et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998;50: 164–168.

    CAS  PubMed  Google Scholar 

  62. Leibson CL, Rocca WA, Hanson VA, et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann N Y Acad Sci 1997;826: 422–427.

    CAS  PubMed  Google Scholar 

  63. Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53: 1937–1942.

    CAS  PubMed  Google Scholar 

  64. Xu WL, Qiu CX, Wahlin A, et al. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 2004;63: 1181–1186.

    CAS  PubMed  Google Scholar 

  65. Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61: 661–666.

    PubMed  Google Scholar 

  66. 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: 1256–1262.

    CAS  PubMed  Google Scholar 

  67. Haan MN, Mungas DM, Gonzalez HM, et al. Prevalence of dementia in older Latinos: the influence of type 2 diabetes mellitus, stroke and genetic factors. J Am Geriatr Soc 2003;51: 169–177.

    PubMed  Google Scholar 

  68. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70: 341–367.

    CAS  PubMed  Google Scholar 

  69. Picard F, Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nute 2002;22: 167–197.

    CAS  Google Scholar 

  70. Wallum BJ, Taborsky GJ, Jr., Porte D, Jr., et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987;64: 190–194.

    CAS  PubMed  Google Scholar 

  71. Frolich L, Blum-Degen D, Riederer P, et al. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann N Y Acad Sci 1999;893: 290–293.

    CAS  PubMed  Google Scholar 

  72. 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: 311–328.

    CAS  PubMed  Google Scholar 

  73. 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: 809–822.

    CAS  PubMed  Google Scholar 

  74. Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord 2006;20: 298–301.

    CAS  PubMed  Google Scholar 

  75. 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: 902–904.

    CAS  PubMed  Google Scholar 

  76. Eckman EA, Eckman CB. Abeta-degrading enzymes: modulators of Alzheimer’s disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 2005;33: 1101–1105.

    CAS  PubMed  Google Scholar 

  77. Leissring MA. Proteolytic degradation of the amyloid beta-protein: the forgotten side of Alzheimer’s disease. Curr Alzheimer Res 2006;3: 431–435.

    CAS  PubMed  Google Scholar 

  78. Cook DG, Leverenz JB, McMillan PJ, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 2003;162: 313–319.

    CAS  PubMed  Google Scholar 

  79. 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 (Washington) 2005;44: 6513–6525.

    CAS  Google Scholar 

  80. 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: 1425–1434.

    CAS  PubMed  Google Scholar 

  81. 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: 4162–4167.

    CAS  PubMed  Google Scholar 

  82. Pedersen WA, McMillan PJ, Kulstad JJ, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006;199: 265–273.

    CAS  PubMed  Google Scholar 

  83. Panza F, Capurso C, D’Introno A, et al. Serum total cholesterol as a biomarker for Alzheimer’s disease: mid-life or late-life determinations? Exp Gerontol 2006;41: 805–806.

    CAS  PubMed  Google Scholar 

  84. Notkola IL, Sulkava R, Pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 1998;17: 14–20.

    CAS  PubMed  Google Scholar 

  85. Wolozin B, Kellman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Archives of Neurology 2000; 57: 1439–1443.

    CAS  PubMed  Google Scholar 

  86. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: the cholesterol connection. Nature Neuroscience 2003;6: 345–351.

    CAS  PubMed  Google Scholar 

  87. Wollmer MA, Streffer JR, Lutjohann D, et al. ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease. Neurobiol Aging 2003;24: 421–426.

    CAS  PubMed  Google Scholar 

  88. Hamilton G, Proitsi P, Jehu L, et al. Candidate gene association study of insulin signaling genes and Alzheimer’s disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 2007;144: 508–516.

    Google Scholar 

  89. Scacchi R, Pinto A, Gambina G, et al. The peroxisome proliferator-activated receptor gamma (PPAR-gamma2) Pro12Ala polymorphism is associated with higher risk for Alzheimer’s disease in octogenarians. Brain Res 2007;1139: 1–5.

    CAS  PubMed  Google Scholar 

  90. Wahrle SE, Jiang H, Parsadanian M, et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 2004;279: 40987–40993.

    CAS  PubMed  Google Scholar 

  91. Hirsch-Reinshagen V, Zhou S, Burgess BL, et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem 2004;279: 41197–41207.

    CAS  PubMed  Google Scholar 

  92. Xu Q, Bernardo A, Walker D, et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 2006;26: 4985–4994.

    CAS  PubMed  Google Scholar 

  93. Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 2005;280: 43224–43235.

    CAS  PubMed  Google Scholar 

  94. Hirsch-Reinshagen V, Maia LF, Burgess BL, et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem 2005;280: 43243–43256.

    CAS  PubMed  Google Scholar 

  95. Wahrle SE, Jiang H, Parsadanian M, et al. Deletion of Abcal increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 2005;280: 43236–43242.

    CAS  PubMed  Google Scholar 

  96. Wahrle SE, Jiang H, Parsadanian M, et al. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 2008;Epub ahead of print.

  97. 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: 1431–1434.

    CAS  PubMed  Google Scholar 

  98. Zelcer N, Khanlou N, Clare R, et al. Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver × receptors. Proc Natl Acad Sci U S A 2007;104: 10601–10606.

    CAS  PubMed  Google Scholar 

  99. 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: 146–153.

    CAS  PubMed  Google Scholar 

  100. 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: 1903–1909.

    CAS  PubMed  Google Scholar 

  101. 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: 605–614.

    CAS  PubMed  Google Scholar 

  102. 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: 47626–47632.

    CAS  PubMed  Google Scholar 

  103. Arakawa R, Hayashi M, Remaley AT, et al. Phosphorylation and stabilization of ATP binding cassette transporter A1 by synthetic amphiphilic helical peptides. J Biol Chem 2004;279: 6217–6220.

    CAS  PubMed  Google Scholar 

  104. Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001;294: 1354–1357.

    CAS  PubMed  Google Scholar 

  105. Nathan BP, Jiang Y, Wong GK, et al. Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein. Brain Res 2002;928: 96–105.

    CAS  PubMed  Google Scholar 

  106. DeMattos RB, Curtiss LK, Williams DL. A minimally lipidated form of cell-derived apolipoprotein E exhibits isoform-specific stimulation of neurite outgrowth in the absence of exogenous lipids or lipoproteins. J Biol Chem 1998;273: 4206–4212.

    CAS  PubMed  Google Scholar 

  107. Fagan AM, Bu G, Sun Y, et al. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem 1996;271: 30121–30125.

    CAS  PubMed  Google Scholar 

  108. Holtzman DM, Pitas RE, Kilbridge J, et al. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci U S A 1995;92: 9480–9484.

    CAS  PubMed  Google Scholar 

  109. Nathan BP, Bellosta S, Sanan DA, et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 1994;264: 850–852.

    CAS  PubMed  Google Scholar 

  110. Brodbeck J, Balestra ME, Saunders AM, et al. Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons. Proc Natl Acad Sci U S A 2008;105: 1343–1346.

    CAS  PubMed  Google Scholar 

  111. Akiyama H, Barger S, Bamum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21: 383–421.

    CAS  PubMed  Google Scholar 

  112. Cooper NR, Bradt BM, O’Barr S, et al. Focal inflammation in the brain: role in Alzheimer’s disease. Immunol Res 2000;21: 159–165.

    CAS  PubMed  Google Scholar 

  113. Rogers J, Webster S, Lue LF, et al. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 1996;17: 681–686.

    CAS  PubMed  Google Scholar 

  114. Rogers J, Shen Y. A perspective on inflammation in Alzheimer’s disease. Ann N Y Acad Sci 2000;924: 132–135.

    CAS  PubMed  Google Scholar 

  115. 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: 462–473.

    CAS  PubMed  Google Scholar 

  116. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006;12: 1005–1015.

    CAS  PubMed  Google Scholar 

  117. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease-a double-edged sword. Neuron 2002;35: 419–432.

    CAS  PubMed  Google Scholar 

  118. Bernardo A, Minghetti L. PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des 2006;12: 93–109.

    CAS  PubMed  Google Scholar 

  119. Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta 2007;1771: 1031–1045.

    CAS  PubMed  Google Scholar 

  120. Heneka MT, Klockgether T, Feinstein DL. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci 2000;20: 6862–6867.

    CAS  PubMed  Google Scholar 

  121. Loane DJ, Deighan BF, Clarke RM, et al. Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain. Neurobiol Aging 2007.

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Authors and Affiliations

  1. Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, 44106, Cleveland, Ohio

    Gary Landreth, Qingguang Jiang & Shweta Mandrekar

  2. Department of Neurology, Molecular Neurobiology Unit, University of Munster, 48149, Munster, Germany

    Michael Heneka

  3. Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, 44106, Cleveland, OH

    Gary Landreth

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  1. Gary Landreth
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  2. Qingguang Jiang
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  3. Shweta Mandrekar
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  4. Michael Heneka
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Correspondence to Gary Landreth.

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Landreth, G., Jiang, Q., Mandrekar, S. et al. PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics 5, 481–489 (2008). https://doi.org/10.1016/j.nurt.2008.05.003

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  • Issue Date: July 2008

  • DOI: https://doi.org/10.1016/j.nurt.2008.05.003

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Key Words

  • Peroxisome proliferator-activated receptor gamma
  • thiazolidinedione
  • Alzheimer’s disease
  • amyloid beta
  • inflammation
  • apolipoprotein E
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