University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Hiv And Antiretrovirals In The Central Nervous System: Molecular Mechanisms Of Cognitive Impairment Anna Louise Stern University of Pennsylvania,
[email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Neuroscience and Neurobiology Commons, and the Virology Commons Recommended Citation Stern, Anna Louise, "Hiv And Antiretrovirals In The Central Nervous System: Molecular Mechanisms Of Cognitive Impairment" (2017). Publicly Accessible Penn Dissertations. 2594. https://repository.upenn.edu/edissertations/2594 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2594 For more information, please contact
[email protected]. Hiv And Antiretrovirals In The Central Nervous System: Molecular Mechanisms Of Cognitive Impairment Abstract HIV-associated neurocognitive disorder (HAND) describes a wide range of cognitive impairments experienced by up to 55% of HIV+ individuals despite viral suppression by combined antiretroviral therapy. Reasons for the persistence of this disease are unknown, but may be related to both the presence of HIV- infected macrophages in the central nervous system as well as neurotoxicity of antiretroviral drugs. In this thesis, we identified two independent mechanisms of HIV-associated and antiretroviral-associated toxicity that may each contribute distinctly to HAND neuropathogenesis. First, we showed that β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which may play a role in the onset and progression of Alzheimer’s Disease, was both increased in HIV+ patient brains and required for HIV-associated neurotoxicity in vitro. The BACE1 cleavage target amyloid precursor protein (APP) also mediated toxicity and was required for neuroprotective effects of BACE1 inhibition.