title: HIV-1 Tat inhibits neprilysin and elevates amyloid beta.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Laboratory Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Rempel
authors.forename: Lynn
authors.initials: L
authors.lastname: Pulliam
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D015696:Gene Products, tat / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D016229:Amyloid beta-Peptides; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D015260:Neprilysin; D003545:Cysteine