Search

The p75 neurotrophin receptor (p75(NTR)) is involved in neuronal functions ranging from induction of apoptosis and growth inhibition to the promotion of survival. p75(NTR) expression is induced in the central nervous system (CNS) by a range of pathological conditions, where it seems to have a role in neuronal death and axonal growth inhibition. The cellular mechanisms driving p75(NTR) expression in cell lines and primary neurons is Sp1 dependent (Ramos et al. [2007] J. Neurosci. 27:1498). In this study, we analyzed the spatiotemporal profile of p75(NTR) expression after an ischemic lesion induced by cortical devascularization (CD). Our results show that p75(NTR) expression occurs in isolated neurons of the ischemic lesion site. The p75(NTR+) neurons presented morphological alterations and active caspase-3 staining. Some p75(NTR+) neurons were also positive for sortilin. The peak of p75(NTR) expression was localized 3 days postlesion (3DPL) in the penumbra. Sp1 transcription factor nuclear localization was observed in p75(NTR+) neurons. The overall level of Sp1 expression was increased until 14DPL on the ipsilateral hemisphere. With primary cortical neurons, we demonstrated that p75(NTR) expression is induced by excitotoxic stress and correlated with increased Sp1 abundance. We conclude that p75(NTR) expression is localized in selected neurons of the ischemic lesion and that these neurons are probably condemned to apoptotic cell death. In primary neuronal culture, it is clear that excitotoxity and Sp1 are involved in induction of p75(NTR) expression, although, in vivo, some additional mechanisms are likely to be involved in the control of p75(NTR) expression in specific neurons in Vivo. (C) 2009 Wiley-Liss, Inc.

Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA. Fil: Angelo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Aguirre, Alejandra Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Aviles Reyes, Rolando Xavier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Villarreal, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Lukin, Jeronimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Melendez, Matías. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Université Claude Bernard Lyon 1; Francia Fil: Vanasco, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Barker, Philip A.. McGill University; Canadá Fil: Alvarez, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Epstein, Alberto Luis. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Université Claude Bernard Lyon 1; Francia Fil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Ramos, Alberto Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia ; Argentina

S100B is a soluble protein secreted by astrocytes that exerts pro-survival or pro-apoptotic effects depending on the concentration reached in the extracellular millieu. The S100B receptor termed RAGE (for receptor for advanced end glycation products) is highly expressed in the developing brain but is undetectable in normal adult brain. In this study, we show that RAGE expression is induced in cortical neurons of the ischemic penumbra. Increased RAGE expression was also observed in primary cortical neurons exposed to excitotoxic glutamate (EG). S100B exerts effects on survival pathways and neurite extension when the cortical neurons have been previously exposed to EG and these S100B effects were prevented by anti-RAGE blocking antibodies. Furthermore, nuclear factor kappa B (NF-κB) is activated by S100B in a dose- and RAGE-dependent manner and neuronal death induced by NF-κB inhibition was prevented by S100B that restored NF-κB activation levels. Together, these findings suggest that excitotoxic damage can induce RAGE expression in neurons from ischemic penumbra and demonstrate that cortical neurons respond to S100B through engagement of RAGE followed by activation of NF-κB signaling. In addition, basal NF-κB activity in neurons is crucial to modulate the extent of pro-survival or pro-death S100B effects.

Sleep apnea (SA) can be effectively managed in humans but it is recognized that when left untreated, SA causes long-lasting changes in neuronal circuitry in the brain. Recent neuroimaging studies gave suggested that these neuronal changes are also present even in patients successfully treated for the acute effects of SA. The cellular mechanisms that account for these changes are not certain but animal models of intermittent hypoxia (IH) during sleep have shown neuronal death and impairment in learning and memory. Reactive gliosis has a drastic effect on neuronal survival and circuitry and in this study we examined the neuro-glial response in brain areas affected by SA. Glial and neuronal alterations were analyzed after 1, 3, 5 and 10 days of exposure to IH (8 h/day during the sleep phase, cycles of 6 min each, 10-21% O-2) and observed significant astroglial hyperplasia and hypertrophy in parietal brain cortex and hippocampus by studying gliofibrillary acidic protein, Vimentin, S100B and proliferating cell nuclear antigen expression. In addition, altered morphology, reduced dendrite branching and caspase activation were observed in the CA-1 hippocampal and cortical ( layers IV-V) pyramidal neurons at short exposure times (1-3 days). Surprisingly, longer exposure to IH reduced the neuronal death rate and increased neuronal branching in the presence of persistent reactive gliosis. Up-regulation of hypoxia inducible factor 1 alpha (HIF-1 alpha) and mdr-1, a HIF-1 alpha target gene, were observed and increased expression of receptor for advanced end glycated products and its binding partner S100B were also noted. Our results show that a low number of hypoxic cycles induce reactive gliosis and neuronal death whereas continuous exposure to IH cycles reduced the rate of neuronal death and induced neuronal branching on surviving neurons. We hypothesize that HIF-1 alpha and S100B glial factor may improve neuronal survival under hypoxic conditions and propose that the death/survival/re-growth process observed here may underlie brain circuitry changes in humans with SA.