Abstract
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.
Keywords:
Amyloid beta; Blood–brain barrier; HIV-1.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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Amyloid beta-Peptides / metabolism*
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Benzamides / pharmacology
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Blood-Brain Barrier / metabolism
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Blood-Brain Barrier / virology
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Brain / metabolism
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Brain / virology
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Cell Line
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Cognitive Dysfunction / virology
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Dioxoles / pharmacology
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Dynamins / antagonists & inhibitors
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Dynamins / metabolism*
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Endothelial Cells / metabolism
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HIV Infections / metabolism*
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HIV-1*
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Humans
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Hydrazones / pharmacology
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Phosphorylation
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RNA Interference
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RNA, Small Interfering
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Signal Transduction / drug effects
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Smad2 Protein / antagonists & inhibitors
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Smad2 Protein / metabolism*
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism*
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Vesicular Transport Proteins / antagonists & inhibitors
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism*
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Amyloid beta-Peptides
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Benzamides
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Dioxoles
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Hydrazones
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N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
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RNA, Small Interfering
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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Smad2 Protein
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Transforming Growth Factor beta
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Vesicular Transport Proteins
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early endosome antigen 1
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Dynamins