Human immunodeficiency virus type 1 (HIV-1)-mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury.
Title | Human immunodeficiency virus type 1 (HIV-1)-mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Guha, D, Wagner, MCE, Ayyavoo, V |
Journal | J Neuroinflammation |
Volume | 15 |
Issue | 1 |
Pagination | 126 |
Date Published | 2018 Apr 27 |
ISSN | 1742-2094 |
Keywords | Adult, Aged, AIDS Dementia Complex, Dendrites, Female, Frontal Lobe, HIV-1, Humans, Inflammation, Male, Middle Aged, Neurogranin, Synapses |
Abstract | BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) is a common outcome of a majority of HIV-1-infected subjects and is associated with synaptodendritic damage. Neurogranin (Ng), a postsynaptic protein, and calmodulin (CaM) are two important players of synaptic integrity/functions. The biological role of Ng in the context of HAND is unknown.METHODS: We compared the expression of Ng in frontal cortex (FC) tissues from control and HIV-1-positive subjects with and without HAND by immunohistochemistry, western blot, and qRT-PCR. The interaction between Ng and CaM was analyzed by co-immunoprecipitation. Ng, microtubule-associated protein 2 (MAP2), CaM, CaM-dependent protein kinase II (CaMKII), CREB, synaptophysin (Syp), and synapsin I (Syn I) expressions were evaluated by western blot using FC tissue lysates and differentiated SH-SY5Y (dSH-SY5Y) cells. Identification of inflammatory factors related to Ng loss was accomplished by exposing dSH-SY5Y cells to HIV-1 and mock-infected monocyte-derived macrophage (MDM) supernatants or HIV-1 NLYU2 pseudotyped with VSV-G-Env. Levels of interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, MCP-2, and CXCL5 in MDM supernatants were measured by ELISA. Association of IL-1β and IL-8 to Ng expression in context of HIV-1 infection was evaluated in the presence or absence of neutralizing antibodies against these cytokines.RESULTS: Expression level of Ng was reduced significantly in FC of HAND-positive (HAND+) patients compared to uninfected individuals. Although no difference was found in CaM expression, interaction between Ng and CaM was reduced in HAND+ patients, which was associated with decreased level of CaMKII, a downstream signaling molecule of CaM pathway. This in turn resulted in reduction of synaptic markers, Syp and Syn I. HIV-1 infection directly had no considerable effect on dysregulation of Ng expression in dSH-SY5Y cells, whereas high amount of pro-inflammatory IL-1β and IL-8 in HIV-1-infected MDM supernatants was associated with significant reduction in Ng expression.CONCLUSIONS: Synaptic damage in HAND+ patients could be a result of abrogation of Ng through HIV-1-induced inflammation that dysregulates Ng-CaM interaction and downstream signaling cascades associated with synaptodendritic functions. This is the first study evaluating the potential role of Ng in the context of HIV-1 neuropathogenesis. |
DOI | 10.1186/s12974-018-1160-2 |
Alternate Journal | J Neuroinflammation |
PubMed ID | 29703241 |
PubMed Central ID | PMC5923011 |
Grant List | U01 AI035042 / AI / NIAID NIH HHS / United States U01 AI035041 / AI / NIAID NIH HHS / United States R01 MH087247 / MH / NIMH NIH HHS / United States UM1 AI035043 / AI / NIAID NIH HHS / United States D43 TW010039 / TW / FIC NIH HHS / United States U01-AI35040 / / National Institute of Allergy and Infectious Diseases / U01 AI035040 / AI / NIAID NIH HHS / United States R01 MH087247 / / National Institute of Mental Health / U01 AI035039 / AI / NIAID NIH HHS / United States D43TW010039 / / National Institutes of Health / |