HIV-1-induced amyloid beta accumulation in brain endothelial cells is attenuated by simvastatin

Archives of Medical Research

Rampersaud²,

Eum

et al. 2014

Self Cite

Background and Aims Increased amyloid deposition in HIV-infected brains may contribute to the pathogenesis of neurocognitive dysfunction in infected patients. We have previously shown that exposure to HIV results in enhanced amyloid β (Aβ) levels in human brain microvascular endothelial cells, suggesting that brain endothelial cells contribute to accumulation of Aβ in HIV-infected brains. Importantly, Aβ not only accumulates in the cytoplasm of HIV-exposed cells but also enters the nuclei of brain endothelial cells. Methods cDNA microarray analysis was performed in order to examine changes in the transcriptional profile associated with Aβ nuclear entry in the presence of HIV-1. Results Gene network analysis indicated that inhibition of nuclear entry of Aβ resulted in enrichment in gene sets involved in apoptosis and survival, endoplasmic reticulum stress response, immune response, cell cycle, DNA damage, oxidative stress, cytoskeleton remodeling and transforming growth factor b (TGFβ) receptor signaling. Conclusions The obtained data indicate that HIV-induced Aβ nuclear uptake affects several cellular stress-related pathways relevant for HIV-induced Aβ pathology.

Section: Introductionsupporting

confidence: 57%

Transcriptional Profile of HIV-induced Nuclear Translocation of Amyloid β in Brain Endothelial Cells

Archives of Medical Research

Rampersaud²,

Eum

et al. 2014

Self Cite

“…HIV-1 is known to increase Aβ accumulation and transfer across HBMEC (Andras et al, 2010, 2012); therefore, we evaluated the impact of HIV-1 on Aβ levels in ECV produced by these cells. For these experiments, HBMEC were exposed to HIV-1 (30 ng/ml) and/or 100 nM Aβ (1–40) HiLyte for 48 h, and Aβ (1–40) HiLyte fluorescence was visualized in ECV isolated from cell culture media.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, the blood-brain barrier (BBB) is crucial for Aβ homeostasis, and plays a role in Aβ accumulation in the brain (Deane and Zlokovic 2007). To support this notion, we demonstrated that HIV-1 could elevate Aβ levels in human brain endothelial cells (HBMEC), and enhance its transendothelial transfer (Andras et al 2010, Andras et al 2012). …”

Section: Introductionmentioning

confidence: 92%

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology

Molecular and Cellular Neuroscience

Léda

Garcia‐Contreras

et al. 2017

Self Cite

HIV-infected brains are characterized by increased amyloid beta (Aβ) deposition. It is believed that the blood-brain barrier (BBB) is critical for Aβ homeostasis and contributes to Aβ accumulation in the brain. Extracellular vesicles (ECV), like exosomes, recently gained a lot of attention as potentially playing a significant role in Aβ pathology. In addition, HIV-1 hijacks the exosomal pathway for budding and release. Therefore, we investigated the involvement of BBB-derived ECV in the HIV-1-induced Aβ pathology in the brain. Our results indicate that HIV-1 increases ECV release from brain endothelial cells as well as elevates their Aβ cargo when compared to controls. Interestingly, brain endothelial cell-derived ECV transferred Aβ to astrocytes and pericytes. Infusion of brain endothelial ECV carrying fluorescent Aβ into the internal carotid artery of mice resulted in Aβ fluorescence associated with brain microvessels and in the brain parenchyma. These results suggest that ECV carrying Aβ can be successfully transferred across the BBB into the brain. Based on these observations, we conclude that HIV-1 facilitates the shedding of brain endothelial ECV carrying Aβ; a process that may increase Aβ exposure of cells of neurovascular unit, and contribute to amyloid deposition in HIV-infected brain.

“…Throughout the study, HBMEC were exposed to HIV-1 particles for 24 h at the p24 level of 30 ng/ml. This type of exposure was shown to be highly effective in stimulation of cellular Aβ levels [12]. Plasma levels of p24 were reported to reach ~5–6 log 10 fg p24/ml in non-treated HIV-1-infected patients, which correspond to ~0.1-1 ng p24/ml [19].…”

Section: Methodsmentioning

confidence: 99%

“…Important observations from our laboratories indicate that exposure to HIV-1 results in enhanced Aβ levels in human brain endothelial cells (HBMEC) and increased its transendothelial transfer [12, 13], suggesting that brain endothelial cells contribute to accumulation of Aβ in HIV-1-infected brains. These observations are consistent with the evidence that brain vascular dysfunction and the blood brain barrier (BBB) are playing important roles in amyloid pathology observed in AD [14].…”

Section: Introductionmentioning

confidence: 99%

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

Experimental Cell Research

Toborek

2014

Self Cite

Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level.