Gonzalo Arboleda

Regulation of ceramide-induced neuronal death: Cell metabolism meets neurodegeneration

The present review explores the role of ceramides in neuronal apoptosis, as well as the recent discovery of the signaling pathways involved in this process placing particular emphasis on the correlation between cellular metabolism and neuronal death. Endogenous levels of ceramides are increased following various pro-apoptotic stimuli which have been identified as potential causes of chronic and acute neurodegenerative diseases. Ceramides induce changes in multiple enzymes and cell signaling components. The early inhibition of the neuronal survival pathway regulated by phosphatidil-inositol-3-kinase/protein kinase B or AKT mediated by ceramide may be a relevant early event in the decision of neuronal survival/death. It may perturb several molecular and metabolic functions. In particular it might decrease glycolysis through rapid modulation of hexokinase activity. This would in turn generate limited amounts of mitochondrial substrates leading to mitochondrial dysfunction and neuronal apoptosis. Subtle and early metabolic alterations caused by inhibition of the PI3K/AKT pathway mediated by ceramide may potentially work with genes associated with neurodegenerative diseases such as Parkinsons and Alzheimers disease. Together they may be determinant steps in downstream events leading to neuronal apoptosis. Therefore, reinforcement of the PI3K/AKT pathway could constitute an important neuroprotective strategy.

Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia.

In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for Alzheimers disease (AD). This hypothesis has important implications for the analysis of AD genetic risk in case-control studies. In the present work, we analyzed common functional polymorphisms in three synaptic plasticity-related genes (brain-derived neurotrophic factor, BDNF Val66Met; catechol-O-methyl transferase, COMT Val158; ubiquitin carboxyl-terminal hydroxylase, UCHL1 S18Y) in a sample of 102 AD cases and 168 age and sex matched controls living in Bogotá, Colombia. There was not association between UCHL1 polymorphism and AD in our sample. We have found an initial association with BDNF polymorphism in familial cases and with COMT polymorphism in male and sporadic patients. These initial associations were lost after Bonferroni correction for multiple testing. Unadjusted results may be compatible with the expected functional effect of variations in these genes on pathological memory and cognitive dysfunction, as has been implicated in animal and cell models and also from neuropsychological analysis of normal subjects carriers of the AD associated genotypes. An exploration of functional variants in these and in other synaptic plasticity-related genes (a synaptogenomics approach) in independent larger samples will be important to discover new genes associated with AD.

Exploration of genetic susceptibility factors for Parkinson’s disease in a South American sample

1Neurosciences Research Group, School of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogota, Colombia 2Department of Internal Medicine, 3Department of Pediatrics, 4Department of Pathology, School of Medicine, Universidad Nacional de Colombia, Bogota, Colombia 5MSc Program in Neurosciences, Universidad Nacional de Colombia, Bogota, Colombia 6Present address: Biomedical Science Research Group, School of Medicine, Universidad Antonio Narino, Bogota, Colombia

Differential regulation of AKT, MAPK and GSK3β during C2-ceramide-induced neuronal death

Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinsons disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death. In the present paper we have analysed the contribution of PI3K/AKT-GSK3β and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C(2)-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3). We demonstrated that C(2)-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3β). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C(2)-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3β. In conclusion, C(2)-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3β and neuronal death, changes that are counteracted by IGF-1.

Apolipoprotein E genotyping in a sample of Colombian patients with Alzheimer's disease

Abstract Apolipoprotein E e4 (APOEe4) allele has been associated with an increased risk for Alzheimers disease (AD) in diverse populations. Few studies have been carried out in Hispano-Americans and results are inconclusive due to ethnic diversity. This study determined the frequency of APOE alleles in a group of 61 Caucasian-Mestizos patients with probable AD, and 61 age- and sex-matched controls. APOEe4 frequency was 36.8% for patients, and 8.2% for controls (P

The neonatal progeroid syndrome (Wiedemann–Rautenstrauch): A model for the study of human aging?

The Wiedemann-Rautenstrauch syndrome (WRS) characterises a premature aging syndrome in which several features of human aging are apparent at birth therefore allowing their grouping as a neonatal progeroid condition. This differentiates WRS from other progeroid entities such as Hutchinson-Gilford progeria syndrome (HGPS) in which characteristics of premature aging become apparent some time after birth. The etiology of WRS remains unknown. Some studies have observed an autosomal recessive mode of inheritance. Several studies analysing telomere length and lamin A gene have not revealed any alterations. However, mutations in LMNA have been reported in several other atypical progeroid syndromes. Based on these observations, several hypothesis could be withdrawn concerning the etiology of WRS. The study of genes associated with lamin A metabolism, such as Zmpste24, and the metabolic pathways associated with insulin, such as protein kinase B or AKT, are of particular interest. We believe that WRS characteristics indicate that discovery of the gene and the metabolic pathway associated with this syndrome will most likely lead to new knowledge about the physiopathology of human aging.

Population frequency for the short tandem repeat loci D18S849, D3S1744, and D12S1090 in Caucasian-Mestizo and African descent populations of Colombia.

Blood samples from 489 unrelated Caucasian Mestizo and 252 individuals of African descent in Colombia were amplified and typed for three short tandem repeat (STR) markers (D12S1090, D3S1744, and D18S849). All markers conformed to Hardy-Weinberg equilibrium expectations in both populations studied. In addition, heterozygosity, mean exclusion chance, polymorphism information content, discrimination power, and the assumption of independence within and between loci were determined. The mean exclusion chance for all three STR markers is 0.9750 in the Caucasian Mestizo population and 0.9731 in the African Colombian Population. The discrimination power is 0.999925 and 0.999911 in the Caucasian Mestizo and African Colombian respectively.

Role of Liver X Receptor in AD Pathophysiology

Alzheimers disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients.

The Wiedemann–Rautenstrauch syndrome (WRS, OMIM: 264090) characterizes a premature aging syndrome in which several features of aging are apparent at birth. We did not find mutations in Lamin A/C (LMNA) gene in four WRS patients, and in particular, we did not find the G608G mutation (GGC > GGT transition) which is associated with most cases with Hutchinson–Gilford progeria (OMIM 176670). These findings suggest that WRS represents a distinct progeroid entity that may be caused by recessive mutations of a different gene.

Association study of polymorphisms in LRP1, tau and 5-HTT genes and Alzheimer's disease in a sample of Colombian patients.

Summary.Analysis of genetic susceptibility factors for Alzheimer’s disease (AD) in populations with different genetic and environmental background may be useful to understand AD etiology. There are few genetic association studies of AD in Latin America. In the present work, we analyzed polymorphisms in 3 candidate genes; the LDL receptor related protein-1, the microtubule-associated protein Tau and the serotonin transporter genes in a sample of 106 Colombian AD patients and 97 control subjects. We did not find a significant allelic or genotypic association with any of the three polymorphisms analyzed using different statistical analysis, including a neural network model or different sample stratifications. To date, APOE polymorphisms are the only genetic risk factors identified for AD in the Colombian population. It may be factible that future combination of high-throughput genotyping platforms and multivariate analysis models may lead to the identification of other genetic susceptibility factors for AD in the Colombian population.