HIV-1 Tat Inhibits Neprilysin and Elevates Amyloid Beta

AIDS. 2005 Jan 28;19(2):127-35. doi: 10.1097/00002030-200501280-00004.

Abstract

Objective: Aging is a risk factor for amyloid beta (Abeta) accumulation and dementia. Since highly active antiretroviral therapies have effectively lengthened the life expectancy of individuals infected with HIV-1, we investigated the affect of HIV-1 Tat, a viral transactivating transcription factor, on Abeta degradation in the brain by neprilysin (NEP), a neuronal endopeptidase.

Design and methods: Using neural cell membrane fractions from human brain aggregates, Tat inhibition of NEP activity was assessed in a fluorescence assay. Following treatment with Tat, conditioned medium of human brain aggregate cultures was assayed for Abeta1-40 by ELISA. We evaluated the potential consequence of Tat inhibition of NEP by immunostaining cortex sections from postmortem human brain for Abeta.

Results: In an in vitro assay, Tat inhibited NEP activity by 80%. The cysteine-rich domain of Tat was essential for NEP inhibition. Recombinant Tat added directly to brain cultures, resulted in a 125% increase in soluble Abeta. Postmortem human brain sections from patients with HIV-1 infection (n = 14; 31-58 years old) had a significant increase in Abeta, compared to controls (n = 5; 30-52 years old). Correlative analysis identified a statistically significant relationship between Abeta load and duration of HIV-1 seropositive status.

Conclusion: We have shown that Tat, which is found in the brains of patients with HIV-1 infection, inhibits the Abeta-degrading enzyme, NEP. Abeta staining was significantly increased in human brain sections from individuals with HIV-1 infection compared to controls. These results have important implications for individuals living and aging with HIV-1 infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AIDS Dementia Complex / genetics
  • AIDS Dementia Complex / metabolism
  • Adult
  • Aging / genetics
  • Aging / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Brain / metabolism*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cysteine / metabolism
  • Frontal Lobe / metabolism
  • Gene Products, tat / genetics*
  • HIV Infections / genetics*
  • HIV Infections / metabolism
  • HIV-1 / genetics*
  • Humans
  • Immunohistochemistry / methods
  • Middle Aged
  • Neprilysin / antagonists & inhibitors*
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Amyloid beta-Peptides
  • Gene Products, tat
  • tat Gene Products, Human Immunodeficiency Virus
  • Neprilysin
  • Cysteine