Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      ADAM Proteins/*metabolism ; Alzheimer Disease/*metabolism ; Amyloid Precursor Protein Secretases/*metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Membrane Proteins/*metabolism ; PPAR alpha/*metabolism; ADAM Proteins/genetics ; ADAM10 Protein ; Alzheimer Disease/genetics ; Amyloid Precursor Protein Secretases/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Brain/drug effects ; Brain/metabolism ; Cells, Cultured ; Female ; Gene Expression/drug effects ; Humans ; Immunoblotting ; Kaplan-Meier Estimate ; Male ; Membrane Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Fluorescence ; Neurons/drug effects ; Neurons/metabolism ; PPAR alpha/agonists ; PPAR alpha/genetics ; Proteolysis ; Pyrimidines/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction
    • Abstract:
      Amyloid precursor protein (APP) derivative β-amyloid (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by β-secretase and γ-secretase generates Aβ. Conversely, the α-secretase "a disintegrin and metalloproteinase" 10 (ADAM10) cleaves APP within the eventual Aβ sequence and precludes Aβ generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPARα, but not PPARβ or PPARγ, decreases the expression of Adam10; and that lentiviral overexpression of PPARα restored ADAM10 expression in Ppara(-/-) neurons. Gemfibrozil, an agonist of PPARα, induced the recruitment of PPARα:retinoid x receptor α, but not PPARγ coactivator 1α (PGC1α), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the α-secretase, as determined by augmented soluble APPα and decreased Aβ production. Accordingly, Ppara(-/-) mice displayed elevated SDS-stable, endogenous Aβ and Aβ1-42 relative to wild-type littermates, whereas 5XFAD mice null for PPARα (5X/α(-/-)) exhibited greater cerebral Aβ load relative to 5XFAD littermates. These results identify PPARα as an important factor regulating neuronal ADAM10 expression and, thus, α-secretase proteolysis of APP.
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    • Grant Information:
      I01 BX003033 United States BX BLRD VA; T32 AG000269 United States AG NIA NIH HHS; R01 NS083054 United States NS NINDS NIH HHS; 5T32 AG000269 United States AG NIA NIH HHS; R01 AT006681 United States AT NCCIH NIH HHS; NS083054 United States NS NINDS NIH HHS; AT6681 United States AT NCCIH NIH HHS
    • Contributed Indexing:
      Keywords: ADAM10; APP; Alzheimer's disease; PPARalpha
    • Accession Number:
      0 (Amyloid beta-Peptides)
      0 (Amyloid beta-Protein Precursor)
      0 (Membrane Proteins)
      0 (PPAR alpha)
      0 (Pyrimidines)
      86C4MRT55A (pirinixic acid)
      EC 3.4.- (Amyloid Precursor Protein Secretases)
      EC 3.4.24.- (ADAM Proteins)
      EC 3.4.24.81 (ADAM10 Protein)
      EC 3.4.24.81 (Adam10 protein, mouse)
    • Publication Date:
      Date Created: 20150617 Date Completed: 20151026 Latest Revision: 20181113
    • Publication Date:
      20240829
    • Accession Number:
      PMC4500265
    • Accession Number:
      10.1073/pnas.1504890112
    • Accession Number:
      26080426