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.
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Acknowledgement
We would like to thank Katherine A. Estes for preparation of drugs for administration to mice, and Seiko Ikezu, Kaitlin Ingraham, Megan Varnum, and Robert Freilich for manuscript editing.
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Susan Swindells reports receiving research grants or contracts from or was a consultant for Abbott Pharmaceuticals, Bavarian Nordic, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer, and Tibotec Therapeutics. The other authors have no potential conflict of interest with this article.
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This work is supported in part by NIH R01 MH083523, R01MH072539, and P01 NS043985 (TI). Drug supports: Pfizer, Inc. for nelfinavir (AG1343), Abbott Laboratory for Kaletra®, and NIH AIDS Research and Reference Reagent Program for amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.
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Lan, X., Kiyota, T., Hanamsagar, R. et al. The Effect of HIV Protease Inhibitors on Amyloid-β Peptide Degradation and Synthesis in Human Cells and Alzheimer’s Disease Animal Model. J Neuroimmune Pharmacol 7, 412–423 (2012). https://doi.org/10.1007/s11481-011-9304-5
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DOI: https://doi.org/10.1007/s11481-011-9304-5