Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Grand Forks, ND, 58203, USA.
J Neuroimmune Pharmacol. 2021 Mar;16(1):159-168. doi: 10.1007/s11481-019-09862-1. Epub 2019 Jul 23.
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.
抗逆转录病毒疗法（ART）有效地提高了 HIV-1 感染者的长期生存率。然而，HIV-1 相关神经认知障碍（HAND）的患病率增加了，HIV-1 感染者的阿尔茨海默病（AD）的临床表现和病理特征也增加了。虽然潜在机制尚不清楚，但慢性暴露于 ART 药物与 AD 样症状和病理的发展有关。ART 药物根据其控制 HIV-1 水平的作用机制进行分类。所有的 ART 药物都是有机化合物，可以分为弱酸性或弱碱性，这些物理化学性质可能对 ART 药物诱导的 AD 样病理学至关重要，因为弱碱性药物在内溶酶体中积累，弱碱性药物可以使发生淀粉样变的内溶酶体去酸化，内溶酶体去酸化增加淀粉样β（Aβ）蛋白的产生并减少 Aβ 的降解。在这里，我们研究了 ART 药物对大鼠原代培养神经元内溶酶体 pH 和 Aβ 水平的影响。使内溶酶体去酸化的 ART 药物增加了 Aβ 水平，而使内溶酶体酸化的 ART 药物则降低了 Aβ 水平。用粘脂素瞬时受体电位（TRPML）通道激动剂 ML-SA1 酸化内溶酶体可阻断 ART 药物引起的 Aβ 水平升高。此外，ART 药物诱导的内溶酶体去酸化增加了内溶酶体的大小；这些作用被 ML-SA1 诱导的内溶酶体酸化所阻断。这些结果表明，ART 药物诱导的内溶酶体去酸化在 ART 药物诱导的淀粉样变形成中起重要作用，内溶酶体酸化可能会减轻 HIV-1 阳性人群中接受使内溶酶体去酸化的 ART 药物的 AD 样病理。
