title: Fenofibrate reduces amyloidogenic processing of APP in APP/PS1 transgenic mice via PPAR-α/PI3-K pathway.
abstract: The peroxisome proliferator-activated receptor alpha (PPAR-α), a member of the family of ligand-activated nuclear hormone receptors, plays a relevant role in the development of Alzheimer's disease (AD). To better understand the role of PPAR-α in AD, we examined the ability of fenofibrate (a PPAR-α agonist) to regulate amyloid precursor protein (APP) processing in APP/PS1 transgenic mice. After intragastric administration of fenofibrate into 3-month-old APP/PS1 transgenic mice for 6 months, and the levels of relative proteins were quantified by quantitative reverse transcription-PCR, Western blotting and ELISA. We found that fenofibrate increased the expression of PPAR-α, and decreased beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) mRNA and protein levels, and also reduced soluble APPβ (sAPPβ) and amyloid-β 42 (Aβ42) releases. However. fenofibrate did not modify the levels of APP and presenilin 1 (PS1). Furthermore, LY294002, the phosphoinositide 3-kinase (PI3-K) inhibitor, suppressed the effects of fenofibrate on BACE-1, sAPPβ, and Aβ42, but not PPAR-α. Our data suggest that fenofibrate may reduce the amyloidogenic processing of APP in APP/PS1 transgenic mice via PPAR-α/PI3-K pathway.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: zhanghua0303@hotmail.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Special Wards, The Affiliated Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Pei-feng
authors.initials: PF
authors.lastname: Qiao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Feng-li
authors.initials: FL
authors.lastname: Zhao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: yongyanpro@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D011345:Fenofibrate / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D019869:Phosphatidylinositol 3-Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D011345:Fenofibrate
keywords: Amyloid precursor protein; Amyloid-β; Beta-site amyloid precursor protein cleaving enzyme 1; Fenofibrate; Peroxisome proliferator-activated receptor alpha; Phosphoinositide 3-kinase