PMID- 24491918 OWN - NLM STAT- MEDLINE DCOM- 20140605 LR - 20220408 IS - 1090-2422 (Electronic) IS - 0014-4827 (Print) IS - 0014-4827 (Linking) VI - 323 IP - 1 DP - 2014 Apr 15 TI - HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-beta/Smad signaling. PG - 66-76 LID - S0014-4827(14)00047-0 [pii] LID - 10.1016/j.yexcr.2014.01.027 [doi] AB - 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 (Abeta) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or Abeta 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-beta/Smad effectively attenuated HIV-1-induced Abeta accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Abeta involves the dynamin-dependent EEA1 and TGF-beta/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Andras, Ibolya E AU - Andras IE AD - Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 1011 NW 15th Street, Gautier Building, Room 528, Miami, FL 33136-1019, United States. Electronic address: iandras@med.miami. FAU - Toborek, Michal AU - Toborek M AD - Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 1011 NW 15th Street, Gautier Building, Room 528, Miami, FL 33136-1019, United States. Electronic address: mtoborek@med.miami.edu. LA - eng GR - R01 CA133257/CA/NCI NIH HHS/United States GR - R01 MH063022/MH/NIMH NIH HHS/United States GR - MH063022/MH/NIMH NIH HHS/United States GR - P30AI073961/AI/NIAID NIH HHS/United States GR - R01 DA027569/DA/NIDA NIH HHS/United States GR - NS39254/NS/NINDS NIH HHS/United States GR - R01 NS039254/NS/NINDS NIH HHS/United States GR - P30 AI073961/AI/NIAID NIH HHS/United States GR - R01 MH098891/MH/NIMH NIH HHS/United States GR - R01 MH072567/MH/NIMH NIH HHS/United States GR - DA027569/DA/NIDA NIH HHS/United States GR - MH098891/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140131 PL - United States TA - Exp Cell Res JT - Experimental cell research JID - 0373226 RN - 0 (4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide) RN - 0 (Amyloid beta-Peptides) RN - 0 (Benzamides) RN - 0 (Dioxoles) RN - 0 (Hydrazones) RN - 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Transforming Growth Factor beta) RN - 0 (SMAD2 protein, human) RN - 0 (Smad2 Protein) RN - 0 (Transforming Growth Factor beta) RN - 0 (Vesicular Transport Proteins) RN - 0 (early endosome antigen 1) RN - EC 3.6.5.5 (Dynamins) SB - IM MH - Active Transport, Cell Nucleus/physiology MH - Amyloid beta-Peptides/*metabolism MH - Benzamides/pharmacology MH - Blood-Brain Barrier/metabolism/virology MH - Brain/metabolism/virology MH - Cell Line MH - Cognitive Dysfunction/virology MH - Dioxoles/pharmacology MH - Dynamins/antagonists & inhibitors/*metabolism MH - Endothelial Cells/metabolism MH - HIV Infections/*metabolism MH - *HIV-1 MH - Humans MH - Hydrazones/pharmacology MH - Phosphorylation MH - RNA Interference MH - RNA, Small Interfering MH - Receptors, Transforming Growth Factor beta/antagonists & inhibitors MH - Signal Transduction/drug effects MH - Smad2 Protein/antagonists & inhibitors/*metabolism MH - Transforming Growth Factor beta/antagonists & inhibitors/*metabolism MH - Vesicular Transport Proteins/antagonists & inhibitors/genetics/*metabolism PMC - PMC4019515 MID - NIHMS577886 OTO - NOTNLM OT - Amyloid beta OT - Blood-brain barrier OT - HIV-1 EDAT- 2014/02/05 06:00 MHDA- 2014/06/06 06:00 PMCR- 2015/04/15 CRDT- 2014/02/05 06:00 PHST- 2013/09/23 00:00 [received] PHST- 2014/01/19 00:00 [revised] PHST- 2014/01/22 00:00 [accepted] PHST- 2014/02/05 06:00 [entrez] PHST- 2014/02/05 06:00 [pubmed] PHST- 2014/06/06 06:00 [medline] PHST- 2015/04/15 00:00 [pmc-release] AID - S0014-4827(14)00047-0 [pii] AID - 10.1016/j.yexcr.2014.01.027 [doi] PST - ppublish SO - Exp Cell Res. 2014 Apr 15;323(1):66-76. doi: 10.1016/j.yexcr.2014.01.027. Epub 2014 Jan 31.