Neurocognitive impairments in HIV-infected individuals, collectively known as HIV-Associated Neurocognitive Impairments (or HAND) remains a significant problem in the era of Combined Antiretroviral Therapy (CART). In many HIV-infected individuals there is evidence of accelerated aging, including aberrant processing of amyloid precursor protein (APP). These disruptions seem to result in accumulations of pathogenic forms of amyloid- () in brain and are thus likely to also decrease the formation of soluble APP? (sAPP?), an important neurotrophic peptide. Our preliminary data suggest that accumulations of sphingolipids and complex glycolipids in intracellular compartments accelerates A formation by enhancing the activity of - and ?- secretases (that process APP to A), and by perturbing the intracellular trafficking / clearance of A. Previously we have documented accumulations of multiple sphingolipid species in HIV-infected individuals. These combined findings prompted us to determine if the accumulations of sphingolipid products in endosomes, lysosomes and/or autophagosomes are associated with aberrant APP processing, increased A deposition and decreased sAPP? in the setting of HIV-infection. In this application we propose a comprehensive approach to address this question, using human brain tissues, cellular/molecular approaches, and transgenic model systems to determine if increased brain levels of these lipid metabolites shifts APP processing to a more amyloidogenic (A) and less trophic (sAPP?) pheotype and if interventions that target sphingolipid metabolism can reverse these effects.

Public Health Relevance

People infected with the Human Immunodeficiency Virus (HIV) are at increased risk for cognitive impairments that are collectively termed HIV-Associated Neurocognitive Impairments (or HAND). Accumulating evidence is beginning to show that a significant number of people infected with HIV are at risk for accelerated brain aging. One manifestation of accelerated brain aging is an increase in the brain deposition of a protein known as amyloid-beta (A). This deposition normally increases with age, but appears to be accelerated by 20-30 years in people infected with HIV. These deposits can disrupt brain functions and may contribute to cognitive impairment in people infected with HIV. Additionally, the production of A disallows the formation of a protein known a soluble APP alpha, (sAPP?), which protects neurons. This study proposes to determine the extent to which the production of these proteins is modified by HIV-infection, and the HIV-associated mechanisms that may perturb the formation of these proteins. Several pathways are targeted that may have therapeutic potential to slow brain aging in this population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
4R01MH096636-04
Application #
9089693
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Joseph, Jeymohan
Project Start
2013-07-19
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Ubaida-Mohien, Ceereena; Lamberty, Benjamin; Dickens, Alex M et al. (2017) Modifications in acute phase and complement systems predict shifts in cognitive status of HIV-infected patients. AIDS 31:1365-1378
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Yoo, S-W; Bae, M; Tovar-Y-Romo, L B et al. (2017) Hippocampal encoding of interoceptive context during fear conditioning. Transl Psychiatry 7:e991
Hategan, Alina; Bianchet, Mario A; Steiner, Joseph et al. (2017) HIV Tat protein and amyloid-? peptide form multifibrillar structures that cause neurotoxicity. Nat Struct Mol Biol 24:379-386
Ubaida-Mohien, Ceereena; Lamberty, Benjamin; Dickens, Alex M et al. (2017) Informatic interrogation of CSF proteomic profiles from HIV-infected subjects implicates acute phase and complement systems in shifting cognitive status. AIDS :
Piepenbrink, Michael S; Samuel, Memorie; Zheng, Bo et al. (2016) Humoral Dysregulation Associated with Increased Systemic Inflammation among Injection Heroin Users. PLoS One 11:e0158641
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Steiner, Joseph P; Bachani, Muznabanu; Wolfson-Stofko, Brett et al. (2016) Erratum to: Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection. Neurotherapeutics 13:237
Steiner, Joseph P; Bachani, Muznabanu; Wolfson-Stofko, Brett et al. (2015) Interaction of paroxetine with mitochondrial proteins mediates neuroprotection. Neurotherapeutics 12:200-16

Showing the most recent 10 out of 17 publications