HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation

Patrick J. Gannon, Cagla Akay-Espinoza, Alan C. Yee, Lisa A. Briand, Michelle A. Erickson, Benjamin Gelman, Yan Gao, Norman J. Haughey, M. Christine Zink, Janice E. Clements, Nicholas S. Kim, Gabriel Van De Walle, Brigid K. Jensen, Robert Vassar, R. Christopher Pierce, Alexander J. Gill, Dennis L. Kolson, J. Alan Diehl, Joseph L. Mankowski, Kelly L. Jordan-Sciutto

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)91-109
Number of pages19
JournalAmerican Journal of Pathology
Volume187
Issue number1
DOIs
StatePublished - Jan 1 2017

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HIV Protease Inhibitors
Amyloid beta-Protein Precursor
Endoplasmic Reticulum Stress
Up-Regulation
Enzymes
Central Nervous System
Eukaryotic Initiation Factor-2
HIV
Eukaryotic Initiation Factors
Unfolded Protein Response
Aptitude
Macaca
Cricetulus
Amyloid
Endoplasmic Reticulum
Ovary
Rodentia
Phosphorylation
Pharmaceutical Preparations
Neurocognitive Disorders

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. / Gannon, Patrick J.; Akay-Espinoza, Cagla; Yee, Alan C.; Briand, Lisa A.; Erickson, Michelle A.; Gelman, Benjamin; Gao, Yan; Haughey, Norman J.; Zink, M. Christine; Clements, Janice E.; Kim, Nicholas S.; Van De Walle, Gabriel; Jensen, Brigid K.; Vassar, Robert; Pierce, R. Christopher; Gill, Alexander J.; Kolson, Dennis L.; Diehl, J. Alan; Mankowski, Joseph L.; Jordan-Sciutto, Kelly L.

In: American Journal of Pathology, Vol. 187, No. 1, 01.01.2017, p. 91-109.

Research output: Contribution to journalArticle

Gannon, PJ, Akay-Espinoza, C, Yee, AC, Briand, LA, Erickson, MA, Gelman, B, Gao, Y, Haughey, NJ, Zink, MC, Clements, JE, Kim, NS, Van De Walle, G, Jensen, BK, Vassar, R, Pierce, RC, Gill, AJ, Kolson, DL, Diehl, JA, Mankowski, JL & Jordan-Sciutto, KL 2017, 'HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation', American Journal of Pathology, vol. 187, no. 1, pp. 91-109. https://doi.org/10.1016/j.ajpath.2016.09.006
Gannon, Patrick J. ; Akay-Espinoza, Cagla ; Yee, Alan C. ; Briand, Lisa A. ; Erickson, Michelle A. ; Gelman, Benjamin ; Gao, Yan ; Haughey, Norman J. ; Zink, M. Christine ; Clements, Janice E. ; Kim, Nicholas S. ; Van De Walle, Gabriel ; Jensen, Brigid K. ; Vassar, Robert ; Pierce, R. Christopher ; Gill, Alexander J. ; Kolson, Dennis L. ; Diehl, J. Alan ; Mankowski, Joseph L. ; Jordan-Sciutto, Kelly L. / HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. In: American Journal of Pathology. 2017 ; Vol. 187, No. 1. pp. 91-109.
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AU - Briand, Lisa A.

AU - Erickson, Michelle A.

AU - Gelman, Benjamin

AU - Gao, Yan

AU - Haughey, Norman J.

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AU - Kim, Nicholas S.

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AU - Jordan-Sciutto, Kelly L.

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