Efavirenz Promotes β-Secretase Expression and Increased Aβ1-40,42 via Oxidative Stress and Reduced Microglial Phagocytosis: Implications for HIV Associated Neurocognitive Disorders (HAND)

doi:10.1371/journal.pone.0095500

Paper

Efavirenz Promotes β-Secretase Expression and Increased Aβ1-40,42 via Oxidative Stress and Reduced Microglial Phagocytosis: Implications for HIV Associated Neurocognitive Disorders (HAND)

Published Apr 23, 2014 · Lecia A M Brown, Jingji Jin, Darren Ferrell

PLoS ONE

Q1 SJR score

58

Citations

5

Influential Citations

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Abstract

Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aβ), and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.

In Vitro Study

Rigorous Journal

Study Snapshot

Efavirenz, a key component of the EFV-containing cART regimen, promotes increased amyloid-beta production and decreased clearance, potentially contributing to HIV-associated neurocognitive disorders.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Efavirenz Promotes β-Secretase Expression and Increased Aβ1-40,42 via Oxidative Stress and Reduced Microglial Phagocytosis: Implications for HIV Associated Neurocognitive Disorders (HAND)

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Citations

The Influence of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial Activity, Lipid Content, and Fatty-Acid-Binding Protein Levels in Microglial HMC3 Cells

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