The effect of HIV protease inhibitors on amyloid-β peptide degradation and synthesis in human cells and Alzheimer's disease animal model

Xiqian Lan, Tomomi Kiyota, Richa Hanamsagar, Yunlong Huang, Scott Andrews, Hui Peng, Jialin C. Zheng, Susan Swindells, George A. Carlson, Tsuneya Ikezu

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDSdefining illness in affected individuals. However, chronic ARTtreated patients frequently develop age-dependent complications, including dementia, diabetes, and hyperlipidemia: all risk factors of Alzheimer's disease. Importantly, the effect of ART compounds on amyloid generation and clearance has never been systematically examined. Nine prescribed HIV protease inhibitors were tested for their effect on amyloid-β peptide (Aβ) clearance in primary cultured human monocyte-derived macrophages. Atazanavir, ritonavir, and saquinavir modestly inhibited of Aβ degradation, while lopinavir, nelfinavir, and ritonavir enhanced secretion of undigested Aβ after phagocytosis. Lopinavir, nelfinavir, ritonavir, and saquinavir inhibited endogenous Aβ40 production from primary cultured human cortical neurons, which were associated with reduction in Beta-site APP Converting Enzyme 1 (BACE1) and γ-secretase enzyme activities. However, ARTcompounds showed little inhibition of purified BACE1 activity in vitro, suggesting the indirect effect of ART compounds on BACE1 activity in neurons. Finally, nefinavir or lopinavir/ritonavir (Kaletra) were orally administered for 30 days into APP SCID mice expressing a double mutant form of APP 695 (KM670/671NL + V717F) in homozygosity for the scid allele of Prkdc. There was no difference in beta-amyloidosis by ART drug administration as determined by both immunohistochemistry and ELISA measurements although the therapeutic doses of the ART compounds was present in the brain. These data demonstrated that ART drugs can inhibit Aβ clearance in macrophages and Aβ production in neurons, but these effects did not significantly alter Aβ accumulation in the mouse brain.

Original languageEnglish (US)
Pages (from-to)412-423
Number of pages12
JournalJournal of Neuroimmune Pharmacology
Volume7
Issue number2
DOIs
StatePublished - Jun 2012

Keywords

  • Alzheimer's disease
  • Amyloid-β peptide
  • Animal model
  • Antiretroviral therapy
  • Macrophage
  • Neuron

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Fingerprint Dive into the research topics of 'The effect of HIV protease inhibitors on amyloid-β peptide degradation and synthesis in human cells and Alzheimer's disease animal model'. Together they form a unique fingerprint.

  • Cite this