title: HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.
abstract: Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced β-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.
authors.affiliation: Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gannon
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Cagla
authors.initials: C
authors.lastname: Akay-Espinoza
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Yee
authors.affiliation: Department of Psychology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Briand
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Erickson
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Van De Walle
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Brigid K
authors.initials: BK
authors.lastname: Jensen
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.affiliation: Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Pierce
authors.affiliation: Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Mankowski
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: jordank@upenn.edu.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008251:Macaca; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D017320:HIV Protease Inhibitors; D008869:Microtubule-Associated Proteins; D019438:Ritonavir; D019892:eIF-2 Kinase