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Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes

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Abstract

Antiretroviral therapeutics (ART) have effectively increased the long-term survival of HIV-1 infected individuals. However, the prevalence of HIV-1 associated neurocognitive disorders (HAND) has increased and so too have clinical manifestations and pathological features of Alzheimer’s disease (AD) in people living with HIV-1/AIDS. Although underlying mechanisms are not clear, chronic exposure to ART drugs has been implicated in the development of AD-like symptoms and pathology. ART drugs are categorized according to their mechanism of action in controlling HIV-1 levels. All ART drugs are organic compounds that can be classified as being either weak acids or weak bases, and these physicochemical properties may be of central importance to ART drug-induced AD-like pathology because weak bases accumulate in endolysosomes, weak bases can de-acidify endolysosomes where amyloidogenesis occurs, and endolysosome de-acidification increases amyloid beta (Aβ) protein production and decreases Aβ degradation. Here, we investigated the effects of ART drugs on endolysosome pH and Aβ levels in rat primary cultured neurons. ART drugs that de-acidified endolysosomes increased Aβ levels, whereas those that acidified endolysosomes decreased Aβ levels. Acidification of endolysosomes with the mucolipin transient receptor potential (TRPML) channel agonist ML-SA1 blocked ART drug-induced increases in Aβ levels. Further, ART drug-induced endolysosome de-acidification increased endolysosome sizes; effects that were blocked by ML-SA1-induced endolysosome acidification. These results suggest that ART drug-induced endolysosome de-acidification plays an important role in ART drug-induced amyloidogenesis and that endolysosome acidification might attenuate AD-like pathology in HIV-1 positive people taking ART drugs that de-acidify endolysosomes.

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Funding

This study was funded by the National Institute of General Medical Sciences (P30GM100329 and U54GM115458), the National Institute of Mental Health (R01MH100972 and R01MH105329), the National Institute of Neurological Diseases and Stroke (R01NS065957), and the National Institute of Drug Abuse (2R01DA032444).

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  1. Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Grand Forks, ND, 58203, USA

    Liang Hui, Yan Ye, Mahmoud L. Soliman, Koffi L. Lakpa, Nicole M. Miller, Zahra Afghah, Jonathan D. Geiger & Xuesong Chen

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  1. Liang Hui
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  2. Yan Ye
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  3. Mahmoud L. Soliman
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Correspondence to Xuesong Chen.

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Conflict of Interest

Liang Hui declares that he has no conflict of interest. Yan Ye declares that she has no conflict of interest. Mahmoud Soliman declares that he has no conflict of interest. Koffi L. Lakpa declares that he has no conflict of interest. Nicole M. Miller declares that she has no conflict of interest. Zahra Afghah declares that she has no conflict of interest. Jonathan D. Geiger declares that he has no conflict of interest. Xuesong Chen declares that he has no conflict of interest.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the University of North Dakota Animal Care and Use Committee adherent with the Guide for the Care and Use of Laboratory Animals (NIH publication number 80–23).

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Hui, L., Ye, Y., Soliman, M.L. et al. Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes. J Neuroimmune Pharmacol 16, 159–168 (2021). https://doi.org/10.1007/s11481-019-09862-1

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