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

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 (A?) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or A? 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-?/Smad effectively attenuated HIV-1-induced A? accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of A? involves the dynamin-dependent EEA1 and TGF-?/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level.

SUBMITTER: Andras IE 

PROVIDER: S-EPMC4019515 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature