title: Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.
abstract: Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Aβ plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Aβ elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Aβ1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Aβ1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 μM) generally increase Aβ generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Aβ1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Aβ found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).
authors.affiliation: Neuroimmunology Laboratory, Department of Psychiatry and Neurosciences, College of Medicine, University of South Florida, Tampa, FL 33612, USA. bgiunta@health.usf.edu
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Demian F
authors.initials: DF
authors.lastname: Obregon
authors.forename: Lucy
authors.initials: L
authors.lastname: Lam
authors.forename: Lisa
authors.initials: L
authors.lastname: Le
authors.forename: JingJi
authors.initials: J
authors.lastname: Jin
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernandez
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology; D015497:HIV-1; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D044966:Anti-Retroviral Agents