HIV Tat impairs neurogenesis through functioning as a notch ligand and activation of notch signaling pathway

Yan Fan, Xiang Gao, Jinhui Chen, Ying Liu, Johnny J. He

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3, 5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo. Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics.

Original languageEnglish (US)
Pages (from-to)11362-11373
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number44
DOIs
StatePublished - Nov 2 2016

Fingerprint

Neurogenesis
HIV
Ligands
Neurons
Stem Cells
Conditioned Culture Medium
Astrocytes
Cell Differentiation
Hot Temperature
tat Gene Products
Parahippocampal Gyrus
Doxycycline
Dentate Gyrus
Brain
Luciferases
Reporter Genes
Recombinant Proteins
Transgenic Mice
Cell Movement
Cysteine

Keywords

  • HIV Tat
  • MCMD
  • Neurogenesis
  • Neuron progenitor cells
  • Notch ligand
  • Notch receptor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

HIV Tat impairs neurogenesis through functioning as a notch ligand and activation of notch signaling pathway. / Fan, Yan; Gao, Xiang; Chen, Jinhui; Liu, Ying; He, Johnny J.

In: Journal of Neuroscience, Vol. 36, No. 44, 02.11.2016, p. 11362-11373.

Research output: Contribution to journalArticle

Fan, Yan ; Gao, Xiang ; Chen, Jinhui ; Liu, Ying ; He, Johnny J. / HIV Tat impairs neurogenesis through functioning as a notch ligand and activation of notch signaling pathway. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 44. pp. 11362-11373.
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