Dataset Information

HIV-1 gp120 impairs spatial memory through CREB

ABSTRACT: HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1 and BDNF genes, we found that CREB dephosphorylation causes PGC1 and BDNF loss of functions. Our data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram that inhibits the phosphodiesterase protein 4 (PDE4) and restores CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Neuron Associated Cell

DISEASE(S): Acquired Immunodeficiency Syndrome

SUBMITTER: Carmen Merali

LAB HEAD: Salim Merali, Ph.D.

PROVIDER: PXD031891 | Pride | 2022-06-09

REPOSITORIES: Pride

ACCESS DATA

Publications

HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein.

Shrestha Jenny J Santerre Maryline M Allen Charles N S CNS Arjona Sterling P SP Merali Carmen C Mukerjee Ruma R Chitrala Kumaraswamy Naidu KN Park Jin J Bagashev Asen A Bui Viet V Eugenin Eliseo A EA Merali Salim S Kaul Marcus M Chin Jeannie J Sawaya Bassel E BE

Frontiers in aging neuroscience 20220509

HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria <i>cristae</i>, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mec ...[more]

PMID: 35615594

Similar Datasets

Project description:Background: SH-SY5Y cells exhibit a neuronal phenotype when treated with all-trans retinoic acid (RA), but the molecular mechanism of activation in the signaling pathway mediated by phosphatidylinositol 3-kinase (PI3K) is not sufficiently understood. To shed new light on the mechanism, we comprehensively compared the gene expression profiles between SK-N-SH cells and two subtypes of SH-SY5Y cells (SH-SY5Y-A and SH-SY5Y-E), each of which showed a different phenotype during RA-mediated differentiation. Results: SH-SY5Y-A cells differentiated in the presence of RA, whereas RA-treated SH-SY5Y-E cells required additional treatment with brain-derived neurotrophic factor (BDNF) for full differentiation. In combination with perturbation using a PI3K inhibitor, LY294002, we identified 386 genes and categorized them into two clusters dependent on the PI3K signaling pathway during RA-mediated differentiation in SH-SY5Y-A cells. Transcriptional regulation of the gene cluster was greatly reduced in SK-N-SH cells or partially impaired in SH-SY5Y-E cells in coincidence with a defect in the neuronal phenotype of these cell lines. Additional stimulation with BDNF induced a set of neural genes which were down-regulated in RA-treated SH-SY5Y-E cells but were abundant in the differentiated SH-SY5Y-A cells. Conclusions: We identified the gene clusters controlled by PI3K- and TRKB-mediated signaling pathways during differentiation in two subtypes of SH-SY5Y cells. TRKB-mediated bypass pathway compensates for the impaired neural functions generated by defects in several signaling pathways including PI3K in SH-SY5Y-E cells. The expression profiling data are useful for further studies to elucidate the signal transduction-transcriptional network including PI3K and/or TRKB. Experiment Overall Design: Human neuroblastomas, SK-N-SH (HTB-11) and SH-SY5Y-A cells (CRL-2266) were obtained from the American Type Culture Collection (ATCC). We also obtained SH-SY5Y-E cells (EC94030304) from the European Collection of Cell Cultures (ECACC). Tissue culture cells were maintained in D-MEM/F12 1:1 mixture supplemented with 15% FBS (Fetal Bovine Serum) and 1% NEAA (Non-essential amino acid) in a 5% CO2 humidified incubator at 37oC. The culture medium was changed twice a week. For the RA-inducible experiment, random culture cells from two clone subtypes of SH-SY5Y and SK-N-SH were seeded in laminin coated culture dishes (BioCoat Laminin Cellware; BD Biosciences, Billerica, MA, USA) for 1 day and then transferred to a medium containing 10 μM of RA in the presence or the absence of LY294002 (10μM) for five days. For BDNF-induced sequential differentiation of the SH-SY5Y-E strain, cells were washed with D-MEM/F12 twice after five days in the presence of RA and then incubated with 50 ng/ml of BDNF in D-MEM/F12 without serum for three days.

Project description:The chemokine receptor CCR5 is a major co-receptor for human immunodeficiency virus 1 (HIV-1) mediating infection of target cells1,2. Beyond its function as co-receptor, CCR5 also influences the course of HIV disease and progression to AIDS3. However, it is unclear how CCR5 affects HIV-associated damage to the central nervous system (CNS) and development of HIV-associated neurocognitive disorders (HAND) independently of its co-receptor function. Here we show in a transgenic model of brain damage induced by HIV envelope protein gp1204 that genetic ablation of CCR5 prevents neuronal injury and loss and limits microglial activation, but fails to abrogate astrocytosis. CCR5 deficiency also protected gp120-transgenic mice against impairment of spatial learning and memory. Thus, CCR5-deficiency revealed that astrocytosis, a prominent pathological feature of AIDS brains5, can occur independently from neuronal demise and behavioral impairment. Since the viral envelope protein expressed in the transgenic mouse model originated from HIV-1 LAV4, a CXCR4-preferring virus that can infect macrophages6, CCR5 appeared to exert its control of neuronal injury predominantly in an indirect fashion and independently from its function as a co-receptor. Using analysis of genome-wide CNS gene expression we identified a subset of 734 genes that were differentially regulated in association with neuronal injury in the presence of CCR5. This subset of genes indicated that neuronal injury was associated with activation of macrophages and microglia. A set of 1305 genes was only differentially regulated in association with gp120 in the absence of CCR5 and indicated changes to leukocyte function and the anti-viral immune response besides a down-regulation of components in the GABAergic neurotransmission system. Interestingly, the most significantly differentially expressed genes were observed in a separate subset of 461 genes that was regulated in association with gp120 but independently of the CCR5 genotype. The finding that differential regulation of the 461 and 1305 gene sets was not necessarily linked to neuronal damage and loss suggested that altered expression of at least some of these factors may represent a protective adaptive response of the brain to the presence of viral gp120. Additional experiments using quantitative RT-PCR, protein assays and flow cytometry further supported the notion that CCR5 deficiency blunted microglial activation, a hallmark of HIV-associated brain injury7-9 without significantly affecting the expression of viral gp120. These results provide in vivo evidence for a significant role of CCR5 in HIV-associated CNS injury and behavioral impairment that is independent of the molecules’ function as HIV co-receptor. To characterize the neuroprotective effect of CCR5 ablation in the presence of HIV gp120, we next performed a genome-wide gene expression analysis using whole brain RNA preparations of mice from lines 1 and 2. We decided to collect samples from two time points before and after the ages of when we analyzed histopathology (6 months) and behavior (8 to 9 months) in order to identify genes for which differential regulation may be affected by an interaction of HIVgp120 expression and age. Accordingly, we collected brain tissue of gp120tg, CCR5KO x gp120tg, WT and CCR5KO mice at five different ages: 1.5, 3, 6, 12, and 20 (line 1) or 16 (line 2) months.

Dataset Information

HIV-1 gp120 impairs spatial memory through CREB

Publications

HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure