Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes

Liang, Hui; Yan, Yonghong; Soliman, Mahmoud L.; Lakpa, Koffi L.; Miller, Nicole; Afghah, Zahra; Geiger, Jonathan D.; Chen, Xuesong

doi:10.1007/s11481-019-09862-1

Cited by 20 publications

(24 citation statements)

References 58 publications

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“…In overall, animals that were treated with TDF showed milder neurochemical changes than nevirapine-treated mice. These findings are consistent with previous in vitro studies showing that neuronal cell exposed to ARV had an increase Aβ production (Giunta et al, 2011;Brown et al, 2014b;Hui et al, 2019). Although the mechanisms by which ART promote Aβ are still unclear, a recent study by Hui et al (2019) found that nevirapine and TDF cause de-acidification endolysosomes and inhibited clearance of Aβ.…”

Section: Discussionsupporting

confidence: 92%

“…These findings are consistent with previous in vitro studies showing that neuronal cell exposed to ARV had an increase Aβ production (Giunta et al, 2011;Brown et al, 2014b;Hui et al, 2019). Although the mechanisms by which ART promote Aβ are still unclear, a recent study by Hui et al (2019) found that nevirapine and TDF cause de-acidification endolysosomes and inhibited clearance of Aβ. Our findings are corroborate previous studies which showed that ARV treatment induce oxidative damage in mice (Zuena et al, 2013;de Oliveira et al, 2014).…”

Section: Discussionsupporting

confidence: 92%

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Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice

Zulu

Abboussi

Simola

et al. 2020

Acta Neuropsychiatr.

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Objectives: Growing evidence suggested that antiretroviral drugs (ARV) may promote β-amyloid accumulation in HIV‐1‐infected brain and the persistence of HIV-associated neurocognitive disorders (HAND). It has also been shown that lipid peroxidation upregulates β-site APP-cleaving enzyme 1 (BACE1) expression and subsequent promote β-amyloid peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate and nevirapine induces lipid peroxidation thereby promoting BACE1 and β-amyloid generation and consequently impair cognitive function in mice. Methods: Tenofovir disoproxil fumarate or nevirapine were orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, β-site APP cleaving enzyme 1 (BACE1), β-amyloid 1-42 and β-amyloid (Aβ) deposits were measured in the hippocampal tissue upon completion of treatment. Results: Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas tenofovir disoproxil fumarate did not have an effect. Tenofovir disoproxil fumarate and nevirapine administration increased hippocampal lipid peroxidation and β-amyloid 1-42 concentration. Nevirapine further upregulated BACE1 expression and β-amyloid (Aβ) deposits. Conclusion: Our results suggest that chronic exposure to tenofovir disoproxil fumarate and nevirapine contributes to hippocampal lipid peroxidation and β-amyloid accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence HIV-infection. These findings further support a possible link between antiretroviral drug toxicity, β-amyloid accumulation and the persistence of HIV associated neurocognitive disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice

Zulu

Abboussi

Simola

et al. 2020

Acta Neuropsychiatr.

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“…rPMs were exposed to cART (TDF, FTC, and DTG), each at 5 μM for various time points (0–24 h), and assessed for a generation of ROS using the DCFH-DA assay. The rationale for choosing the combination and concentrations of drugs is based on several published reports ( 36 – 38 ). In our previous published study ( 13 ), we have studied the effects of individual and the combinations of TDF, FTC, and DTG on lysosomal function.…”

Section: Resultsmentioning

confidence: 99%

“…Lysosomal dysfunction is shown to correlate with inflammation ( 14 , 15 ). Various studies have demonstrated the role of HIV-1 Tat protein ( 61 ) as well as antiretrovirals ( 38 ) in mediating endolysosomal dysfunction. Findings from our earlier in vitro study demonstrated that cART-mediated activation of microglia involved impaired lysosomal functioning and dysregulated autophagy ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine Reverses Antiretroviral-Mediated Microglial Activation by Attenuating Autophagy-Lysosomal Dysfunction

et al. 2020

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Successful suppression of viral replication by combined antiretroviral therapy (cART) in HIV-1 infected individuals is paradoxically also accompanied by an increased prevalence of HIV-associated neurocognitive disorders (HAND) in these individuals. HAND is characterized by a state of chronic oxidative stress and inflammation. Microglia are extremely sensitive to a plethora of stimuli, including viral proteins and cART. The current study aimed to assess the effects of cART-mediated oxidative stress on the induction of inflammatory responses in microglia. In the present study, we chose a combination of three commonly used antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine, and dolutegravir. We demonstrated that exposure of microglia to the chosen cART cocktail induced generation of reactive oxygen species, subsequently leading to lysosomal dysfunction and dysregulated autophagy, ultimately resulting in the activation of microglia. Intriguingly, the potent antioxidant, N-acetylcysteine, reversed the damaging effects of cART. These in vitro findings were further corroborated in vivo wherein cART-treated HIV transgenic (Tg) rats demonstrated increased microglial activation, exaggerated lysosome impairment, and dysregulated autophagy in the prefrontal cortices compared with HIV Tg rats not exposed to cART. Similar to in vitro findings, the treatment of HIV Tg rats with N-acetylcysteine also mitigated the deleterious effects of cART. Taken together, our findings suggest that oxidative stress-mediated lysosomal dysfunction plays a critical role in the pathogenesis of HAND in drug-treated HIV-infected individuals and that antioxidant-mediated mitigation of oxidative stress could thus be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND.

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“…However, it is not clear whether this accumulation is due to AD-like processes, HIVassociated immunosuppression, Tat protein-induced Aβ elevations, and/or the effects of cART. Published studies suggest that cART has played a significant role in cART induced neurological disorders that, in turn, developed into HAND [65][66][67]. cART formularies have a wide range of toxic effects on neurons, a study comparing two cART formularies showed a significant degeneration of MAP-2 neurons, after being treated with Efavirenz and Atazanavir [68].…”

Section: Development Of Hand Through Cart Therapymentioning

confidence: 99%

The Increase of HIV-1 Infection, Neurocognitive Impairment, and Type 2 Diabetes in The Rio Grande Valley

Garza

Rodrigo

Fernandez

et al. 2020

CHR

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: The Human Immunodeficiency Virus (HIV-1) infection remains a persistent predicament for the State of Texas, ranking seventh among the most documented HIV cases in the United States. In this regard, the Rio Grande Valley (RGV) in South Texas is considered as one of the least investigated areas of the state with respect to HIV infection and HIV associated comorbidities. Considering the 115% increase in average HIV incidence rates per 100,000 within the RGV from 2007-2015, it is worth characterizing this population with respect to their HIV-1 infection, HIV-1 Associated Neurocognitive Disorders (HAND), and the association of treatment with combined antiretroviral therapy (cART). Moreover, the increased rate of Type-2 Diabetes (T2D) in the RGV population is intertwined with that of HIV-1 infection facing challenges due to the lack of knowledge about prevention to inadequate access to healthcare. Hence, the role of T2D in the development of HAND among the people living with HIV (PLWH) in the RGV will be reviewed to establish a closer link between T2D and HAND in cART-treated patients of the RGV.

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Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes

Cited by 20 publications

References 58 publications

Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice

Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice

N-Acetylcysteine Reverses Antiretroviral-Mediated Microglial Activation by Attenuating Autophagy-Lysosomal Dysfunction

The Increase of HIV-1 Infection, Neurocognitive Impairment, and Type 2 Diabetes in The Rio Grande Valley

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