Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders - PubMed (original) (raw)

Review

Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders

Brian Giunta et al. Mol Brain. 2011.

Abstract

Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Aβ plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Aβ elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Aβ1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Aβ1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 μM) generally increase Aβ generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Aβ1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Aβ found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).

PubMed Disclaimer

Figures

Figure 1

Figure 1

ART medications increase Aβ generation in cultured neuronal cells. Total Aβ 1-40,42 peptides were analyzed in conditioned media from SweAPP N2a cells by ELISA (n = 2 for each condition). Data are represented as a mean ± SEM percentage of Aβ 1-40,42 peptides secreted 18 hours after antiretroviral treatment relative to control (untreated). One-way ANOVA followed by post hoc comparison revealed significant increases in Aβ 1-40,42 production following 3TC/Indinavir, 3TC/Abacavir, and Indinavir/Abacavir treatements (concentration of 10 μM for each individual compound; p < 0.05).

Figure 2

Figure 2

ART medications inhibit microglial phagocytosis of Aβ1-42 peptides. N9 microglia were treated with "aged" FITC-tagged Aβ 1-42 (300 nM) in complete medium for 120 min in the presence of 10 μM concentrations of antiretrovirals. Total FITC-Aβ1-42 peptides were analyzed by fluorescence from conditioned media (extracellular; top) and cell lysates (phagosomal/cell associated; bottom). Data are represented as the relative mean ± SEM fluorescence (n = 4 for each condition presented). When measuring extracellular FITC-tagged Aβ 1-42, one-way ANOVA followed by post hoc comparison showed significantly higher levels following all antiretroviral treatments, as compared to control (p < 0.05). When measuring cell associated FITC-tagged Aβ 1-42, one-way ANOVA followed by post hoc comparison showed significantly lower levels following Indinavir, Abacavir, AZT/3TC, AZT/Abacavir, 3TC/Indinavir, and Indinavir/Abacavir, as compared to control (p < 0.05).

Similar articles

Cited by

References

    1. Goodkin K, Fletcher MA, Cohen N. Clinical aspects of psychoneuroimmunology. Lancet. 1995;345(8943):183–4. - PubMed
    1. Schouten J. et al.HIV-1 infection and cognitive impairment in the cART era: a review. AIDS. 2011;25(5):561–75. doi: 10.1097/QAD.0b013e3283437f9a. - DOI - PubMed
    1. Xu J, Ikezu T. The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol. 2009;4(2):200–12. doi: 10.1007/s11481-008-9136-0. - DOI - PMC - PubMed
    1. Shapshak P. et al.Elevated expression of IFN-gamma in the HIV-1 infected brain. Front Biosci. 2004;9:1073–81. doi: 10.2741/1271. - DOI - PubMed
    1. Ghafouri M. et al.HIV-1 associated dementia: symptoms and causes. Retrovirology. 2006;3:28. doi: 10.1186/1742-4690-3-28. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources