Antiretroviral drugs promote amyloidogenesis by de-acidifying endolysosomes
| Autor: | Jonathan D. Geiger, Yan Ye, Xuesong Chen, Zahra Afghah, Liang Hui, Mahmoud L. Soliman, Koffi L. Lakpa, Nicole M. Miller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chronic exposure Agonist Amyloid TRPML Intravital Microscopy medicine.drug_class Amyloid beta Anti-HIV Agents Immunology Neuroscience (miscellaneous) Endosomes Pharmacology Hippocampus Article Rats Sprague-Dawley 03 medical and health sciences Transient receptor potential channel Neuroblastoma 0302 clinical medicine Cell Line Tumor Immunology and Allergy Medicine Animals Humans Cells Cultured Neurons Amyloid beta-Peptides biology business.industry Chloroquine Amyloidosis Hydrogen-Ion Concentration Antiretroviral therapy Endolysosome Rats 030104 developmental biology Mechanism of action Proteolysis biology.protein medicine.symptom business Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | J Neuroimmune Pharmacol |
| Popis: | 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. Graphical Abstract. |
| Databáze: | OpenAIRE |
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