title: Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice.
abstract: The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPARβ/δ(-/-) mice. Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex.
authors.affiliation: Unitat de Farmacologia, Department de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona, Institut de Biomedicina de la UB, IBUB, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.forename: Jaume
authors.initials: J
authors.lastname: del Valle
authors.forename: David
authors.initials: D
authors.lastname: Porquet
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vieira Santos
authors.forename: Laia
authors.initials: L
authors.lastname: Salvadó
authors.forename: Rosalía
authors.initials: R
authors.lastname: Rodríguez-Rodríguez
authors.forename: Patrícia
authors.initials: P
authors.lastname: Gutiérrez
authors.forename: Marta
authors.initials: M
authors.lastname: Anglada-Huguet
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D048068:PPAR-beta; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C528900:glial fibrillary astrocytic protein, mouse; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse