Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

Abstract

Chemokine receptors, and in particular CXCR4 and CCR5 play a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV)4 associated dementia (HAD). Thus, new insight into the expression of CXCR4 in the central nervous system may help develop therapeutic compounds against HAD. Brain-derived neurotrophic factor (BDNF) is neuroprotective in vitro against two strains of the HIV envelope protein gp120 that binds to CXCR4 or CCR5. Therefore, we examined whether BDNF modulates chemokine receptor expression in vivo. The content of CXCR4 mRNA and proteins was determined in the cerebral cortex and hippocampus of 6-month-old BDNF heterozygous mice and wild type littermates by using polymerase chain reaction and immunohistochemistry, respectively. BDNF heterozygous mice exhibited an increase in CXCR4 mRNA compared to wild type. Histological analyses revealed an up-regulation of CXCR4 immunoreactivity mainly in neurons. Most of these neurons were positive for TrkB, the BDNF receptor with a tyrosine kinase activity. Increases in CXCR4 mRNA levels were observed in 18-month-old BDNF heterozygous mice but not in 7 day-old mice, suggesting that the modulatory role of BDNF occurs only in mature animals. To determine whether BDNF affects also CXCR4 internalization, SH-SY5Y neuroblastoma cells were exposed to BDNF and cell surface CXCR4 levels were measured at various times. BDNF induced CXCR4 internalization within minutes. Lastly, BDNF heterozygous mice showed higher levels of CCR5 and CXCR3 mRNA than wild type in the cerebral cortex, hippocampus and striatum. Our data indicate that BDNF may modulate the availability of chemokine receptors implicated in HIV infection.

CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson’s Disease

“…BDNF is a neurotrophic factor that has been shown to prevent DA loss in animal models of PD (Hyman et al 1991;Altar et al 1992), and to block the neurotoxic effect of CXCR4 agonists (Bachis and Mocchetti 2005;Nosheny et al 2007). Indeed, it has been demonstrated that BDNF reduces the expression of neuronal CXCR4 in vivo Ahmed et al 2008). These data depict a scenario in which DA neurons in the SN may be spared from apoptosis if pro-inflammatory cytokines/chemokines levels are balanced by a sufficient amount of neurotrophic factors.…”

The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning

“…They included two SNPs within the CCL3 (rs1719134 and rs1130371)(Levine 2009), a three-SNP haplotype within the MBL-2 gene (rs1800450, rs1800451, and rs5030737)(Spector et al), and single SNPs within coding or non-coding regions of the CCL2 gene (rs1024611)(Gonzalez et al 2002), TNF-α (rs1800629)(Mathis et al 2008), COMT (rs4680)(Bousman et al 2010, Kumar et al 2011), BDNF (rs6265)(Ahmed et al 2008, Nosheny et al 2007), DBH (rs1611115)(Kumar et al 2011), DR2/ANKK1 - rs1800497)(Kumar et al 2011), DR3 (rs6280), and CXCL12 (rs1801157)(Langford et al 2002, Peng et al 2006). …”

Neurotoxicity of Human Immunodeficiency Virus-1: Viral Proteins and Axonal Transport

“…Neurotoxic actions of viral proteins include an increase in the production of pro-inflammatory cytokines and a reduction of anti-apoptotic neurotrophic factors, such as BDNF and glial-cell derived neurotrophic factor (Nosheny et al, 2006) . Reduction of BDNF culminates in an up-regulation of CXCR4 and CCR5 (Nosheny et al, 2004; Ahmed et al, 2008; Avdoshina et al, 2011), two HIV co-receptors that also promote neuronal apoptosis. In addition, BDNF promotes adult neurogenesis (Li et al, 2008) that is believed to be essential for specific cognitive functions that decline in HIV positive subjects (Venkatesan et al, 2007).…”