[en] Alzheimer's disease (AD) is characterized by the deposition of beta-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 (PPARgamma) 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 PPARgamma agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARgamma agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARgamma represents an important new therapeutic target in treating AD.
Disciplines :
Neurologie
Auteur, co-auteur :
Landreth, Gary; Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. gel2@case.edu
Jiang, Qingguang; Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States
Mandrekar, Shweta; Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States
HENEKA, Michael ; Department of Neurology, Molecular Neurobiology Unit, University of Munster, Munster, 48149, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease.
This work was supported by grants from the National Institutes of Health (Grant nos. AG16704 and AG030482), the American Health Assistance Foundation and the Blanchette Hooker Rockefeller Foundation. MH was supported by grants from the Deutsche Forschungsgemeinschaft (DFG [German Research Foundation]).
Sundararajan S., Jiang Q., Heneka M., et al. PPARgamma as a therapeutic target in central nervous system diseases. Neurochem Int 49 (2006) 136-144
Risner M.E., Saunders A.M., Altman J.F., et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6 (2006) 246
Kersten S., Desvergne B., and Wahli W. Roles of PPARs in health and disease. Nature 405 (2000) 421-424
Bookout A.L., Jeong Y., Downes M., et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126 (2006) 789-799
Lehrke M., and Lazar M. The many faces of PPARgamma. Cell (Cambridge) 123 (2005) 993-999
Maeshiba Y., Kiyota Y., Yamashita K., et al. Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 47 (1997) 29-35
Pedersen W., McMillan P., Kulstad J., et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199 (2006) 265-273
Strum J.C., Shehee R., Virley D., et al. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 11 (2007) 45-51
Glass C.K. Going nuclear in metabolic and cardiovascular disease. Eur J Clin Invest 116 (2006) 556-560
Berger J., and Moller D.E. The mechanisms of action of PPARs. Annu Rev Med 53 (2002) 409-435
Aranda A., and Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev 81 (2001) 1269-1304
Glass C.K., and Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14 (2000) 121-141
Daynes R.A., and Jones D.C. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2 (2002) 748-759
Subbaramaiah K., Lin D.T., Hart J.C., 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 276 (2001) 12440-12448
Li M., Pascual G., and Glass C.K. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 20 (2000) 4699-4707
Pascual G., Fong A.L., Ogawa S., et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437 (2005) 759-763
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 23 (2003) 7504-7509
Lim G.P., Yang F., Chu T., et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 20 (2000) 5709-5714
Heneka M., Sastre M., Dumitrescu-Ozimek L., et al. Acute treatment with the PPARg agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128 (2005) 1442-1453
Pedersen W.A., and Flynn E.R. Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer's disease. Neurobiol Dis 17 (2004) 500-506
Andrews R., and Walker B. Glucocorticoids and insulin resistance: old hormones, new targets. Clinical science (London, England: 1979) 96 (1999) 513-523
Andrews R.C., Herlihy O., Livingstone D.E., et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab 87 (2002) 5587-5593
Pomara N., Greenberg W.M., Branford M.D., et al. Therapeutic implications of HPA axis abnormalities in Alzheimer's disease: review and update. Psychopharmacol Bull 37 (2003) 120-134
Morcos M., Fohr B., Tafel J., et al. Long-term treatment of central Cushing's syndrome with rosiglitazone. Exp Clin Endocrinol Diabetes 115 (2007) 292-297
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 151 (2004) 173-178
Heaney A.P., Fernando M., Yong W.H., et al. Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 8 (2002) 1281-1287
Catrina S.B., Virtanen K., Hallsten K., et al. Effect of rosiglitazone on early-morning plasma cortisol levels. Neuro Endocrinol Lett 26 (2005) 763-764 author reply 765
Watson G.S., Cholerton B.A., Reger M.A., 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 13 (2005) 950-958
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.
Waugh J., Keating G.M., Plosker G.L., et al. Pioglitazone: a review of its use in type 2 diabetes mellitus. Drugs 66 (2006) 85-109
Nissen S.E., and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356 (2007) 2457-2471
Lincoff A.M., Wolski K., Nicholls S.J., et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298 (2007) 1180-1188
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 315 (1997) 1045-1049
Craft S., Asthana S., Schellenberg G., et al. Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology 70 (1999) 146-152
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 903 (2000) 222-228
Sastre M., Dewachter I., Landreth G.E., 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 23 (2003) 9796-9804
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 103 (2006) 443-448
d'Abramo C., Massone S., Zingg J.M., et al. Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. Biochem J 391 (2005) 693-698
Camacho I.E., Serneels L., Spittaels K., et al. Peroxisome proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 24 (2004) 10908-10917
Mosconi L., Tsui W.H., De Santi S., et al. Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 64 (2005) 1860-1867
Reiman E.M., Chen K., Alexander G.E., et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A 101 (2004) 284-289
Reiman E.M., Caselli R.J., 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 98 (2001) 3334-3339
Small G.W., Ercoli L.M., Silverman D.H., et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 97 (2000) 6037-6042
Small G.W., Mazziotta J.C., Collins M.T., et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273 (1995) 942-947
Reiman E.M., Chen K., Alexander G.E., et al. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A 102 (2005) 8299-8302
Bookheimer S.Y., Strojwas M.H., Cohen M.S., et al. Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med 343 (2000) 450-456
Castellani R., Hirai K., Aliev G., et al. Role of mitochondrial dysfunction in Alzheimer's disease. J Neurosci Res 70 (2002) 357-360
Roses A.D., Saunders A.M., Huang Y., et al. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease). Pharmacogenomics J 7 (2007) 10-28
Bogacka I., Xie H., Bray G.A., et al. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54 (2005) 1392-1399
Handschin C., and Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27 (2006) 728-735
Hondares E., Mora O., Yubero P., et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 147 (2006) 2829-2838
Wu Z., Puigserver P., Andersson U., et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98 (1999) 115-124
Kelly L.J., Vicario P.P., Thompson G.M., 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 139 (1998) 4920-4927
Puigserver P., Wu Z., Park C.W., et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92 (1998) 829-839
Houten S.M., and Auwerx J. PGC-1alpha: turbocharging mitochondria. Cell 119 (2004) 5-7
Mootha V.K., Lindgren C.M., Eriksson K.F., et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34 (2003) 267-273
Feinstein D.L., Spagnolo A., Akar C., et al. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key?. Biochem Pharmacol 70 (2005) 177-188
Biessels G.J., Staekenborg S., Brunner E., et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5 (2006) 64-74
Razay G., Vreugdenhil A., and Wilcock G. The metabolic syndrome and Alzheimer disease. Archives of Neurology 64 (2007) 93-96
Razay G., and Wilcock G.K. Hyperinsulinaemia and Alzheimer's disease. Age Ageing 23 (1994) 396-399
Craft S., Peskind E., Schwartz M.W., et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50 (1998) 164-168
Leibson C.L., Rocca W.A., Hanson V.A., et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann N Y Acad Sci 826 (1997) 422-427
Ott A., Stolk R.P., van Harskamp F., et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53 (1999) 1937-1942
Xu W.L., Qiu C.X., Wahlin A., et al. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63 (2004) 1181-1186
Arvanitakis Z., Wilson R.S., Bienias J.L., et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61 (2004) 661-666
Peila R., Rodriguez B.L., and Launer L.J. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51 (2002) 1256-1262
Haan M.N., Mungas D.M., Gonzalez H.M., et al. Prevalence of dementia in older Latinos: the influence of type 2 diabetes mellitus, stroke and genetic factors. J Am Geriatr Soc 51 (2003) 169-177
Willson T.M., Lambert M.H., and Kliewer S.A. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 70 (2001) 341-367
Picard F., and Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 22 (2002) 167-197
Wallum B.J., Taborsky Jr. G.J., Porte Jr. D., et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 64 (1987) 190-194
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 893 (1999) 290-293
Messier C., and Teutenberg K. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast 12 (2005) 311-328
Craft S., Asthana S., Cook D.G., et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 28 (2003) 809-822
Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord 20 (2006) 298-301
Ho L., Qin W., Pompl P.N., et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. Faseb J 18 (2004) 902-904
Eckman E.A., and Eckman C.B. Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 33 (2005) 1101-1105
Leissring M.A. Proteolytic degradation of the amyloid beta-protein: the forgotten side of Alzheimer's disease. Curr Alzheimer Res 3 (2006) 431-435
Cook D.G., Leverenz J.B., McMillan P.J., et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 162 (2003) 313-319
Farris W., Leissring M.A., Hemming M.L., 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) 44 (2005) 6513-6525
Farris W., Mansourian S., Leissring M.A., et al. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol 164 (2004) 1425-1434
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 100 (2003) 4162-4167
Pedersen W.A., McMillan P.J., Kulstad J.J., et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199 (2006) 265-273
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 41 (2006) 805-806
Notkola I.L., Sulkava R., Pekkanen J., et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17 (1998) 14-20
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 57 (2000) 1439-1443
Puglielli L., Tanzi R.E., and Kovacs D.M. Alzheimer's disease: the cholesterol connection. Nature Neuroscience 6 (2003) 345-351
Wollmer M.A., Streffer J.R., Lutjohann D., et al. ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. Neurobiol Aging 24 (2003) 421-426
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 144 (2007) 508-516
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 1139 (2007) 1-5
Wahrle S.E., 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 279 (2004) 40987-40993
Hirsch-Reinshagen V., Zhou S., Burgess B.L., et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem 279 (2004) 41197-41207
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 26 (2006) 4985-4994
Koldamova R., Staufenbiel M., and Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280 (2005) 43224-43235
Hirsch-Reinshagen V., Maia L.F., Burgess B.L., 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 280 (2005) 43243-43256
Wahrle S.E., Jiang H., Parsadanian M., et al. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280 (2005) 43236-43242
Wahrle S.E., 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
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 27 (2006) 1431-1434
Zelcer N., Khanlou N., Clare R., et al. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci U S A 104 (2007) 10601-10606
Piraino G., Cook J.A., 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 26 (2006) 146-153
Calkin A.C., Forbes J.M., Smith C.M., et al. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol 25 (2005) 1903-1909
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 71 (2006) 605-614
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 279 (2004) 47626-47632
Arakawa R., Hayashi M., Remaley A.T., et al. Phosphorylation and stabilization of ATP binding cassette transporter A1 by synthetic amphiphilic helical peptides. J Biol Chem 279 (2004) 6217-6220
Mauch D.H., Nagler K., Schumacher S., et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294 (2001) 1354-1357
Nathan B.P., Jiang Y., Wong G.K., 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 928 (2002) 96-105
DeMattos R.B., Curtiss L.K., and Williams D.L. 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 273 (1998) 4206-4212
Fagan A.M., 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 271 (1996) 30121-30125
Holtzman D.M., Pitas R.E., 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 92 (1995) 9480-9484
Nathan B.P., Bellosta S., Sanan D.A., et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264 (1994) 850-852
Brodbeck J., Balestra M.E., Saunders A.M., 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 105 (2008) 1343-1346
Akiyama H., Barger S., Barnum S., et al. Inflammation and Alzheimer's disease. Neurobiol Aging 21 (2000) 383-421
Cooper N.R., Bradt B.M., O'Barr S., et al. Focal inflammation in the brain: role in Alzheimer's disease. Immunol Res 21 (2000) 159-165
Rogers J., Webster S., Lue L.F., et al. Inflammation and Alzheimer's disease pathogenesis. Neurobiol Aging 17 (1996) 681-686
Rogers J., and Shen Y. A perspective on inflammation in Alzheimer's disease. Ann N Y Acad Sci 924 (2000) 132-135
Colangelo V., Schurr J., Ball M.J., 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 70 (2002) 462-473
Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response?. Nat Med 12 (2006) 1005-1015
Wyss-Coray T., and Mucke L. Inflammation in neurodegenerative disease-a double-edged sword. Neuron 35 (2002) 419-432
Bernardo A., and Minghetti L. PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des 12 (2006) 93-109
Heneka M.T., and Landreth G.E. PPARs in the brain. Biochim Biophys Acta 1771 (2007) 1031-1045
Heneka M.T., Klockgether T., and Feinstein D.L. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci 20 (2000) 6862-6867
Loane D.J., Deighan B.F., Clarke R.M., et al. Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain. Neurobiol Aging (2007)
