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Background <p>Despite increased life expectancy with antiretroviral therapy, people with HIV (PWH) have significantly higher prevalence of comorbid diseases, including neurocognitive impairment. PWH and neurocognitive impairment often show features of Alzheimer’s-like pathologies, including increased brain amyloid-beta (Aβ) and phospho-Tau; it is not known if antiretroviral drugs contribute to the development of these pathologies or potentiate HIV effects. We aimed to investigate whether azidothymidine (AZT), a drug still used by PWH in many resource-limited countries, alters or potentiates HIV-induced Alzheimer’s-like pathologies.</p> Methods <p>Hu-PBL-NSG mice plasma/serum and brain tissues were analyzed to investigate the effects of HIV-1 infection and AZT treatment on viremia, immunosuppression, phospho-Tau, Aβ<sub>42</sub>, neuronal NeuN, endothelial claudin-5, ZO-1, and Aβ transporters [low-density lipoprotein receptor–related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE)] transcription, expression, and proteolytic cleavage. In vitro, we assessed the effects of HIV-1 Tat and AZT on Aβ<sub>42</sub> aggregation, endothelial LRP1 and RAGE expression, Aβ uptake and transport.</p> Results <p>HIV significantly increased brain phospho-Tau (serine199, threonine181, serine396), brain and plasma Aβ<sub>42</sub>, decreased LRP1, NeuN, claudin-5, ZO-1, and increased RAGE transcription and expression, increased soluble(s)LRP1 and decreased sRAGE. AZT treatment of infected animals decreased blood and brain viremia and reduced HIV-induced immunosuppression but had no effect on HIV-induced brain Aβ<sub>42</sub>, phospho-Tau, NeuN, claudin-5, ZO-1, LRP1 or RAGE transcription, expression, or cleavage. AZT treatment of non-infected animals significantly increased phospho-Tau in the brain somatosensory cortex, decreased LRP1, NeuN, claudin-5, and ZO-1, and increased RAGE transcription and expression, increased sLRP1 and decreased sRAGE. Tat decreased LRP1 and increased RAGE expression in brain endothelial cells, and AZT accentuated Tat-induced effects. AZT+Tat significantly increased Aβ aggregation and AZT significantly increased endothelial Aβ<sub>42</sub> uptake/retention.</p> Conclusions <p>HIV and AZT independently dysregulate NeuN, claudin-5, ZO-1, LRP1 and RAGE transcription, expression, and proteolytic cleavage in hu-PBL-NSG mice. Such dysregulation of neuronal nuclei, endothelial tight junction proteins, and Aβ transporters could contribute to increased neurovascular injury and altered Aβ clearance following HIV infection and/or AZT treatment. In the presence of Tat, AZT increased Aβ aggregation. AZT also increased endothelial Aβ uptake/retention, which suggests that AZT may contribute to brain endothelium impairment and dysfunction.</p>

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Effects of HIV and azidothymidine on Alzheimer’s-like pathology and amyloid beta transporters in hu-PBL-NSG mice, brain endothelial amyloid beta uptake and endothelial barrier integrity

  • 期刊论文

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  • 发表日期：

    2026年4月16日

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  • Biju Bhargavan,
  • Narendran Annadurai,
  • Georgette D. Kanmogne

摘要

Background

Despite increased life expectancy with antiretroviral therapy, people with HIV (PWH) have significantly higher prevalence of comorbid diseases, including neurocognitive impairment. PWH and neurocognitive impairment often show features of Alzheimer’s-like pathologies, including increased brain amyloid-beta (Aβ) and phospho-Tau; it is not known if antiretroviral drugs contribute to the development of these pathologies or potentiate HIV effects. We aimed to investigate whether azidothymidine (AZT), a drug still used by PWH in many resource-limited countries, alters or potentiates HIV-induced Alzheimer’s-like pathologies.

Methods

Hu-PBL-NSG mice plasma/serum and brain tissues were analyzed to investigate the effects of HIV-1 infection and AZT treatment on viremia, immunosuppression, phospho-Tau, Aβ42, neuronal NeuN, endothelial claudin-5, ZO-1, and Aβ transporters [low-density lipoprotein receptor–related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE)] transcription, expression, and proteolytic cleavage. In vitro, we assessed the effects of HIV-1 Tat and AZT on Aβ42 aggregation, endothelial LRP1 and RAGE expression, Aβ uptake and transport.

Results

HIV significantly increased brain phospho-Tau (serine199, threonine181, serine396), brain and plasma Aβ42, decreased LRP1, NeuN, claudin-5, ZO-1, and increased RAGE transcription and expression, increased soluble(s)LRP1 and decreased sRAGE. AZT treatment of infected animals decreased blood and brain viremia and reduced HIV-induced immunosuppression but had no effect on HIV-induced brain Aβ42, phospho-Tau, NeuN, claudin-5, ZO-1, LRP1 or RAGE transcription, expression, or cleavage. AZT treatment of non-infected animals significantly increased phospho-Tau in the brain somatosensory cortex, decreased LRP1, NeuN, claudin-5, and ZO-1, and increased RAGE transcription and expression, increased sLRP1 and decreased sRAGE. Tat decreased LRP1 and increased RAGE expression in brain endothelial cells, and AZT accentuated Tat-induced effects. AZT+Tat significantly increased Aβ aggregation and AZT significantly increased endothelial Aβ42 uptake/retention.

Conclusions

HIV and AZT independently dysregulate NeuN, claudin-5, ZO-1, LRP1 and RAGE transcription, expression, and proteolytic cleavage in hu-PBL-NSG mice. Such dysregulation of neuronal nuclei, endothelial tight junction proteins, and Aβ transporters could contribute to increased neurovascular injury and altered Aβ clearance following HIV infection and/or AZT treatment. In the presence of Tat, AZT increased Aβ aggregation. AZT also increased endothelial Aβ uptake/retention, which suggests that AZT may contribute to brain endothelium impairment and dysfunction.