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<p>Neurocognitive impairments occur in about 50% of HIV-infected humans and are associated with Alzheimer’s disease (AD)-like brain pathologies, including increased amyloid-beta1-42(Aβ<sub>42</sub>) and phospho-Tau. We previously demonstrated that HIV-infected humanized mice develop these AD-like pathologies associated with neurodegeneration. The underlying mechanisms are unknown. Here, we investigate whether HIV-induced Aβ and phospho-Tau involve dysregulation of transporters and kinases that regulate Tau phosphorylation and Aβ clearance, and the effects of CCR5 antagonists on these effectors. We analyzed human and animal (humanized mice) brain tissues, microvessels, plasma/serum, and human brain microvascular endothelial cells (HBMEC) for effects of HIV-1 infection, maraviroc treatment, and CCR5 knockdown/overexpression on Aβ, phospho-Tau, low-density lipoprotein receptor–related protein-1(LRP1), receptor for advanced glycation end-products (RAGE), and GSK-3α/β transcription, expression, and activation, LRP1 and RAGE cleavage/shedding, Aβ endothelial uptake and transport/clearance. HIV infection significantly increased phospho-Tau (serine396, serine199, threonine181), Aβ<sub>42</sub> and GSK-3α/β activation in humans and animals’ brain cortex. HIV significantly decreased LRP1 and increased RAGE transcription and expression in brain tissues and microvessels, with accentuated LRP1 and RAGE dysregulation in humans with neurocognitive impairments. HIV significantly increased soluble (s)LRP1 and decreased sRAGE. Maraviroc abrogated HIV-induced CNS GSK-3α/β activation and Tau hyperphosphorylation, prevented LRP1 downregulation and RAGE upregulation, significantly decreased sLRP1 and increased sRAGE, increased Aβ<sub>42</sub> efflux eightfold and decreased brain Aβ<sub>42</sub> levels 11.7-fold. Maraviroc abrogated Aβ<sub>42</sub>-induced decrease in HBMEC tightness, significantly decreased endothelial RAGE, increased LRP1, and Aβ<sub>42</sub> endothelial transport via LRP1 crosstalk. CCR5 knockdown blocked maraviroc-induced increased endothelial Aβ transport. These data suggest that therapeutically targeting CCR5 can abrogate HIV-induced GSK-3α/β activation and phospho-Tau, prevent LRP1 downregulation and shedding and increase brain Aβ efflux/clearance, prevent RAGE upregulation, Aβ brain influx, and AD-like neuropathology.</p>

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Glycogen synthase kinase-3 activation and dysregulation of amyloid transport receptors expression and shedding in HIV-induced Alzheimer’s disease-like pathology: modulatory effects of CCR5 antagonists

  • 期刊论文

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  • 发表日期：

    2025年12月6日

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

摘要

Neurocognitive impairments occur in about 50% of HIV-infected humans and are associated with Alzheimer’s disease (AD)-like brain pathologies, including increased amyloid-beta1-42(Aβ42) and phospho-Tau. We previously demonstrated that HIV-infected humanized mice develop these AD-like pathologies associated with neurodegeneration. The underlying mechanisms are unknown. Here, we investigate whether HIV-induced Aβ and phospho-Tau involve dysregulation of transporters and kinases that regulate Tau phosphorylation and Aβ clearance, and the effects of CCR5 antagonists on these effectors. We analyzed human and animal (humanized mice) brain tissues, microvessels, plasma/serum, and human brain microvascular endothelial cells (HBMEC) for effects of HIV-1 infection, maraviroc treatment, and CCR5 knockdown/overexpression on Aβ, phospho-Tau, low-density lipoprotein receptor–related protein-1(LRP1), receptor for advanced glycation end-products (RAGE), and GSK-3α/β transcription, expression, and activation, LRP1 and RAGE cleavage/shedding, Aβ endothelial uptake and transport/clearance. HIV infection significantly increased phospho-Tau (serine396, serine199, threonine181), Aβ42 and GSK-3α/β activation in humans and animals’ brain cortex. HIV significantly decreased LRP1 and increased RAGE transcription and expression in brain tissues and microvessels, with accentuated LRP1 and RAGE dysregulation in humans with neurocognitive impairments. HIV significantly increased soluble (s)LRP1 and decreased sRAGE. Maraviroc abrogated HIV-induced CNS GSK-3α/β activation and Tau hyperphosphorylation, prevented LRP1 downregulation and RAGE upregulation, significantly decreased sLRP1 and increased sRAGE, increased Aβ42 efflux eightfold and decreased brain Aβ42 levels 11.7-fold. Maraviroc abrogated Aβ42-induced decrease in HBMEC tightness, significantly decreased endothelial RAGE, increased LRP1, and Aβ42 endothelial transport via LRP1 crosstalk. CCR5 knockdown blocked maraviroc-induced increased endothelial Aβ transport. These data suggest that therapeutically targeting CCR5 can abrogate HIV-induced GSK-3α/β activation and phospho-Tau, prevent LRP1 downregulation and shedding and increase brain Aβ efflux/clearance, prevent RAGE upregulation, Aβ brain influx, and AD-like neuropathology.