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The Effect of HIV Protease Inhibitors on Amyloid-β Peptide Degradation and Synthesis in Human Cells and Alzheimer’s Disease Animal Model

Content Provider	PubMed Central
Author	Lan, Xiqian Kiyota, Tomomi Richa, Hanamsagar Huang, Yunlong Andrews, Scott Peng, Hui Zheng, Jialin C. Swindells, Susan Carlson, George A. Ikezu, Tsuneya
Copyright Year	2011
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, 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.
Related Links	http://dx.doi.org/10.1007/s11481-011-9304-5
Ending Page	423
Page Count	12
Starting Page	412
File Format	PDF
ISSN	15571890
e-ISSN	15571904
Journal	Journal of Neuroimmune Pharmacology
Issue Number	2
Volume Number	7
Language	English
Publisher Date	2012-06-01
Access Restriction	Open
Subject Keyword	Immunology Immunology and Allergy Pharmacology Neuroscience (miscellaneous) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Allergy Pharmacology Immunology

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