title: Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide.
abstract: We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. Inducing expression or activating PPARgamma using synthetic agonists of the thiazolinedione family results in a dramatic decrease in the levels of the amyloid-beta (Abeta) peptide in the conditioned medium of neuronal and non-neuronal cells. PPARgamma does not affect expression or activity of any of the secretases involved in the generation of the Abeta peptide but induces a fast, cell-bound clearing mechanism responsible for the removal of the Abeta peptide from the medium. Although PPARgamma expression is generally low in the CNS, induction of PPARgamma expression during inflammation could be beneficial for inducing Abeta clearance. We confirm that the Abeta clearance mechanism can indeed be induced by PPARgamma activation in primary murine-mixed glia and cortical neuronal cultures. Our results suggest that PPARgamma-controlled mechanisms should be explored further as potential drug targets for Alzheimer's disease treatment.
authors.affiliation: Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, Vlaams Interuniversitair Instituut voor Biotechnologie and Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Ira Espuny
authors.initials: IE
authors.lastname: Camacho
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Kurt
authors.initials: K
authors.lastname: Spittaels
authors.forename: Pascal
authors.initials: P
authors.lastname: Merchiers
authors.forename: Diana
authors.initials: D
authors.lastname: Dominguez
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D002839:Chromans / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000737:chemistry; D010450:Endopeptidases / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007668:Kidney; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D000077205:Pioglitazone; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D047488:Retinoid X Receptors / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D016229:Amyloid beta-Peptides; D000813:Anilides; D002839:Chromans; D017077:Culture Media, Conditioned; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D047495:PPAR gamma; D010446:Peptide Fragments; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); D000077154:Rosiglitazone; D014212:Tretinoin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D000077288:Troglitazone; D000077205:Pioglitazone