Original Article HIV-1 TAT Inhibits Microglial Phagocytosis of Aβ Peptide
Brian Giunta, Yuyan Zhu, Huayan Hou, Paul Shapshak, Francisco Fernandez and Jun Tan
Psychoimmunology Laboratory, Institute for Research in Psychiatry and Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, FL 33613, USA.
Received 2 Aug 2007; accepted with revision 10 Sept 2007; available online 1 January 2008
Abstract: Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical neuropsychiatric syndrome that has increased in prevalence in the era of highly active antiretroviral therapy (HAART). Several studies demonstrated increased amyloidosis in brains of HIV patients and suggested that there may be a significant number of long-term HIV survivors with co-morbid Alzheimer's disease (AD) in the future. We show HIV-1 Tat protein inhibits microglial uptake of Aβ1-42 peptide, a process that is enhanced by interferon-gamma (IFN-γ) and rescued by the STAT1 inhibitor (-)-epigallocatechin-3-gallate (EGCG). It is hypothesized that reduced Aβ uptake occurs through IFN-γ mediated STAT1 activation. This process promotes a switch from a phagocytic to an antigen presenting phenotype in microglia through activation of class II transactivator (CIITA). Additionally, we show that HIV-1 Tat significantly disrupts apolipoprotein-3 (Apo-E3) promoted microglial Aβ uptake. As Tat has been shown to directly interact with the low density lipoprotein (LRP) receptor and thus inhibit the uptake of its ligands including apolipoprotein E4 (Apo-E4) and Aβ peptide in neurons, we further hypothesize that a similar inhibition of LRP may occur in microglia. Future studies will be required to fully characterize the mechanisms underlying IFN-γ enhancement of HIV-1 Tats disruption of microglial phagocytosis of Aβ and Apo-E3. (IJCEP708004).
Key words: HIV-associated dementia (HAD), inflammation, AIDS dementia complex (ADC), Interferon-gamma (IFN-γ), green tea, (−)- epigallocatechin-3-gallate (EGCG)
Address all correspondence to: Brian Giunta, MD, Department of Psychiatry and Behavioral Medicine, Psychoimmunology Laboratory, Room 350, University of South Florida College of Medicine, 3515 E Fletcher Ave., Tampa, FL 33613, USA. Tel: 813-974-0616; Fax: 813-974-1130; Email: email@example.com