title: The effect of HIV protease inhibitors on amyloid-β peptide degradation and synthesis in human cells and Alzheimer's disease animal model.
abstract: Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDS-defining illness in affected individuals. However, chronic ART-treated 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, ART compounds 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyota
authors.forename: Richa
authors.initials: R
authors.lastname: Hanamsagar
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.forename: Scott
authors.initials: S
authors.lastname: Andrews
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Jialin C
authors.initials: JC
authors.lastname: Zheng
authors.forename: Susan
authors.initials: S
authors.lastname: Swindells
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000069446:Atazanavir Sulfate; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D061466:Lopinavir / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D019888:Nelfinavir / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir