HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling.
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.
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.
Ibolya E
IE
András
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.
Michal
M
Toborek
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D060825:Cognitive Dysfunction / Q000821:virology; D004149:Dioxoles / Q000494:pharmacology; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D016229:Amyloid beta-Peptides; D001549:Benzamides; D004149:Dioxoles; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D034281:Dynamins
Amyloid beta; Blood–brain barrier; HIV-1