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.

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.