Neuronal apoptosis is a hallmark of AIDS dementia complex (ADC), and may represent a final common pathway of cell death in response to neurotoxins released from HIV-infected macrophages(HIV/MDM). Some forms of neuronal apoptosis are blocked by certain anti-apoptosis members of the bct-2gone family (Bcl-2 & Bcl-xL), which block the intrinsic (mitochondrial-associated) pathway. Neuronal apoptosis may also be blocked by activation of AKT/protein kinase B signaling (AKT/PKB), which acts at points involving the intrinsic and extrinsic (death receptor-associated) apoptosis pathways. How the intrinsic and/or extrinsic apoptosis pathways are involved in neuronal apoptosis in ADC is unknown, and this represents an important gap in our understanding of HIV neuropathogenesis and neuroprotective strategies. We have developed a novel in vitro model for HIV-induced neuronal apoptosis based on a unique human neuronal cell line (NT2.N). We found that Bcl-2 & Bcl-xL as well as activators of neuronal AKT/PKB block HIV/MDM-induced neuronal apoptosis. We have also demonstrated expression of the newly described seven-transmembrane HIV co-receptor APJ in neurons, and found that its native ligand, apelin, activates AKT/PKB and blocks such apoptosis. Finally, we have used a novel single-cell mRNA amplification technique to analyze gene expression in apoptotic neurons in vivo. Our hypothesis is that HIV induced neuronal apoptosis is mediated through specific pathways involving both intrinsic & extrinsic apoptosis mechanisms that may be differentially induced by HIV/MDM and HIV proteins, and that APJ activated signaling may modulate these pathways and mediate neuroprotective responses against effectors of HIV-associated apoptosis.
Our aim i s to better understand the pathways of HIV-induced neuronal apoptosis and the mechanisms of apelin/APJ neuroprotection, through our in vitro model and analysis of gene expression in apoptotic neurons in rive. We will: 1) Determine the pathways of neuronal apoptosis induced by HIV/MDM &: associated neurotoxins; 2) Define the neuroprotective signaling pathways for APJ/apelin against HIV/MDM; and 3) Determine the expression of genes modulating intrinsic & extrinsic apoptosis pathways and neuroprotective pathways in defined subclasses of apoptotic neurons in HIV-infected brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043994-04
Application #
7047908
Study Section
Special Emphasis Panel (ZRG1-AARR-5 (02))
Program Officer
Wong, May
Project Start
2003-04-01
Project End
2007-09-29
Budget Start
2006-04-01
Budget End
2007-09-29
Support Year
4
Fiscal Year
2006
Total Cost
$367,592
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zyskind, Jacob W; Wang, Ying; Cho, Giyong et al. (2015) E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity. J Neurochem 132:742-55
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Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
Gill, Alexander J; Kolson, Dennis L (2013) Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. Crit Rev Immunol 33:307-59
Akay, C; Lindl, K A; Shyam, N et al. (2012) Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex. Neuropathol Appl Neurobiol 38:175-200
White, Michael G; Wang, Ying; Akay, Cagla et al. (2011) Parallel high throughput neuronal toxicity assays demonstrate uncoupling between loss of mitochondrial membrane potential and neuronal damage in a model of HIV-induced neurodegeneration. Neurosci Res 70:220-9
Cook, Denise R; Gleichman, Amy J; Cross, Stephanie A et al. (2011) NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury. J Neurochem 118:1113-23
Gannon, Patrick; Khan, Muhammad Z; Kolson, Dennis L (2011) Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol 24:275-83
Cross, Stephanie A; Cook, Denise R; Chi, Anthony W S et al. (2011) Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection. J Immunol 187:5015-25

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