Acute Colon Inflammation Triggers Primary Motor Cortex Glial Activation, Neuroinflammation, Neuronal Hyperexcitability, and Motor Coordination Deficits.

Neuroinflammation underlies neurodegenerative diseases. Herein, we test whether acute colon inflammation activates microglia and astrocytes, induces neuroinflammation, disturbs neuron intrinsic electrical properties in the primary motor cortex, and alters motor behaviors. We used a rat model of acute colon inflammation induced by dextran sulfate sodium. Inflammatory mediators and microglial activation were assessed in the primary motor cortex by PCR and immunofluorescence assays. Electrophysiological properties of the motor cortex neurons were determined by whole-cell patch-clamp recordings. Motor behaviors were examined using open-field and rotarod tests. We show that the primary motor cortex of rats with acute colon inflammation exhibited microglial and astrocyte activation and increased mRNA abundance of interleukin-6, tumor necrosis factor-alpha, and both inducible and neuronal nitric oxide synthases. These changes were accompanied by a reduction in resting membrane potential and rheobase and increased input resistance and action potential frequency, indicating motor neuron hyperexcitability. In addition, locomotion and motor coordination were impaired. In conclusion, acute colon inflammation induces motor cortex microglial and astrocyte activation and inflammation, which led to neurons' hyperexcitability and reduced motor coordination performance. The described disturbances resembled some of the early features found in amyotrophic lateral sclerosis patients and animal models, suggesting that colon inflammation might be a risk factor for developing this disease.

Association between Apoε4 allele and cardiometabolic and social risk factors with cognitive impairment in elderly population from Bogota / Associação entre o alelo Apoε4 fatores de risco cardiometabólicos e sociais com prejuízo cognitivo em idosos de Bogotá

ABSTRACT Being an ϵ4 carrier in the Apoϵ gene has been suggested as a modifying factor for the interaction between cardio-metabolic, social risk factors, and the development of cognitive impairment. Objective: The main objective of this study was to assess the existence of such interaction in a sample of Bogota's elderly population. Methods: A cross-sectional study was conducted with 1,263 subjects older than 50 years. Each participant was diagnosed by consensus, after neuropsychological and neuropsychiatric evaluations, under a diagnosis of normal cognition, mild cognitive impairment (MCI) according to Petersen's criteria, or dementia according to DSM-IV criteria. Apoϵ was typified and an analysis of MoCA test was performed in each group carrying or not ϵ4 allele. Results: Our study showed that 75% were women with a median age of 68 years (interquartile range 62-74 years) and a median schooling for 6 years (interquartile range 4-12 years). Dementia was related to low education level of ≤5 years OR=11.20 (95%CI 4.99-25.12), high blood pressure (HBP) OR=1.45 (95%CI 1.03-2.05), and age over 70 years OR=7.68 (95%CI 3.49-16.90), independently of being or not an ϵ4 allele carrier. Diabetic subjects with dementia carrying ϵ4 allele showed a tendency to exhibit lower scores on the MoCA test, when compared with noncarriers' diabetic subjects with dementia. Conclusions: The presence of ϵ4 allele does not modify the relationship between cognitive impairment and the different cardio-metabolic and social risk factors, except in diabetic subjects ϵ4 carriers with dementia who showed a tendency to exhibit lower scores of the MoCA test, when compared with noncarriers' diabetic subjects with dementia.

RESUMO Ser um portador ϵ4 no gene Apoϵ tem sido sugerido como um fator modificador da interação entre fatores cardiometabólicos, de risco social e o desenvolvimento de comprometimento cognitivo. Objetivo: O objetivo principal deste trabalho é avaliar a existência de tal interação em uma amostra da população idosa de Bogotá. Métodos: Um estudo transversal foi realizado com 1.263 indivíduos com mais de 50 anos. Cada participante foi diagnosticado por consenso após avaliações neuropsicológicas e neuropsiquiátricas, sob um diagnóstico de cognição normal, comprometimento cognitivo leve de acordo com os critérios de Petersen ou demência de acordo com os critérios do Manual Diagnóstico e Estatístico de Trastornos Mentais (DSM-IV). Apoϵ4 foi tipificada e uma análise do Montréal Cognitive Assessment Test (teste de MoCA) foi realizada em cada grupo portador ou não do alelo ϵ4. Resultados: Nosso estudo mostrou que 75% eram mulheres com idade mediana de 68 anos (intervalo interquartil 62 a 74 anos) e escolaridade mediana de seis anos (intervalo interquartil 4 a 12 anos). A demência estava relacionada ao baixo nível de escolaridade ≤5 anos Odds Ratio (OR)=11,20 (intervalo de confiança — IC95% 4,99-25,12), pressão alta OR=1,45 (IC95% 1,03-2,05) e idade acima de 70 anos OR=7,68 (IC95% 3,49-16,90), independentemente de ser ou não portador do alelo ϵ4. Indivíduos diabéticos com demência portadores do alelo ϵ4 mostraram tendência de exibir pontuações mais baixas no teste MoCA quando comparados com indivíduos diabéticos com demência não portadores do alelo ϵ4. Conclusões: A presença do alelo ϵ4 não modifica a relação entre o comprometimento cognitivo e os diferentes fatores de risco cardiometabólico e social, exceto em diabéticos portadores de ϵ4 com demência, que exibiram tendência a apresentar menores escores no teste MoCA quando comparados com indivíduos diabéticos com demência não portadores do alelo ϵ4.

To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells.

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.

Mild cognitive impairment (MCI) and dementia in a sample of adults in the city of Bogotá / Comprometimento cognitivo leve (CCL) e demência em uma amostra de adultos na cidade de bogotá

ABSTRACT The low prevalence of dementia described in communities is likely due to the low sensitivity of screening tests and an absence of evaluation by specialists. OBJECTIVE: To estimate the prevalence of mild cognitive impairment (MCI) and dementia in adults older than 50 years. METHODS: A two-phase, cross-sectional study was conducted by specialists to evaluate cognition and associated demographic risk factors in 1,235 independent community-dwelling adults from Bogotá. In Phase I, screening was performed using the MMSE and MoCA tests. In Phase II, after application of a comprehensive neuropsychological battery with neurologic and psychiatric evaluations, a cognitive diagnosis was established by consensus. RESULTS: The prevalence found for MCI was 34% and for dementia was 23%. MCI was associated with incomplete high school, OR=1.74 (95%CI=1.23-2.45), and with an age of 70-79 years, OR=1.93 (95%CI=1.47-2.53). A total of 73% of MCI cases were amnestic. Dementia was associated with incomplete primary education, OR=8.98 (95%CI=5.56-14.54), complete primary education, OR=6.23 (95%CI=3.70-10.47), and age older than eighty years, OR=3.49 (95%CI=2.23-5.44). CONCLUSION: The prevalence of dementia found was greater than the rates reported in previous studies. Low educational level was the main risk factor for cognitive impairment and should be considered in strategic planning for the local health system.

RESUMO A baixa prevalência de demência relatada em comunidades deve ser devida ao emprego de testes de rastreio de baixa sensibilidade e à falta da avaliação por especialistas. OBJETIVO: Estimar a prevalência de comprometimento cognitivo leve (CCL) e demência em adultos com idade superior a 50 anos. MÉTODOS: Um estudo transversal de duas fases realizado por especialistas, avaliando a cognição e os fatores de risco demográficos associados, com 1.235 adultos autônomos da comunidade em Bogotá. Em uma Fase I, foram realizados os testes de rastreio MEEM e MoCA. Na Fase II, após uma ampla bateria neuropsicológica com avaliações neurológicas e psiquiátricas, foi estabelecido um diagnóstico cognitivo por consenso. RESULTADOS: A prevalência encontrada de CCL foi de 34% e de demência, de 23%. CCL foi associado a ensino médio incompleto, OR=1,74 (IC 95%=1,23-2,45) e idade entre 70-79 anos, OR=1,93 (IC 95%=1,47-2,53). Entre os casos de CCL, 73% eram amnésticos. A demência foi associada a ensino fundamental incompleto, OR=8,98 (IC 95%=5,56-14,54), ensino fundamental completo, OR=6,23 (IC 95%=3,70-10,47) e idade superior a oitenta anos, OR=3,49 (IC 95%=2,23-5,44). CONCLUSÃO: A prevalência de demência encontrada é maior do que a relatada em estudos prévios. O baixo nível educacional foi o principal fator de risco para declínio cognitivo e deve ser considerado no planejamento estratégico do nosso sistema de saúde.

Neuronal tetraploidization in the cerebral cortex correlates with reduced cognition in mice and precedes and recapitulates Alzheimer's-associated neuropathology.

A controversy exists as to whether de novo-generated neuronal tetraploidy (dnNT) occurs in Alzheimer's disease. In addition, the presence of age-associated dnNT in the normal brain remains unexplored. Here we show that age-associated dnNT occurs in both superficial and deep layers of the cerebral cortex of adult mice, a process that is blocked in the absence of E2F1, a known regulator of cell cycle progression. This blockage correlates with improved cognition despite compromised neurogenesis in the adult hippocampus was confirmed in mice lacking the E2f1 gene. We also show that the human cerebral cortex contains tetraploid neurons. In normal humans, age-associated dnNT specifically occurs in the entorhinal cortex whereas, in Alzheimer, dnNT also affects association cortices prior to neurofibrillary tangle formation. Alzheimer-associated dnNT is likely potentiated by altered amyloid precursor protein (APP) processing as it is enhanced in the cerebral cortex of young APPswe/PS1deltaE9 mice, long before the first amyloid plaques are visible in their brains. In contrast to age-associated dnNT, enhanced dnNT in APPswe/PS1deltaE9 mice mostly affects the superficial cortical layers. The correlation of dnNT with reduced cognition in mice and its spatiotemporal course, preceding and recapitulating Alzheimer-associated neuropathology, makes this process a potential target for intervention in Alzheimer's disease.

Muscle physiology changes induced by every other day feeding and endurance exercise in mice: effects on physical performance.

Every other day feeding (EOD) and exercise induce changes in cell metabolism. The aim of the present work was to know if both EOD and exercise produce similar effects on physical capacity, studying their physiological, biochemical and metabolic effects on muscle. Male OF-1 mice were fed either ad libitum (AL) or under EOD. After 18 weeks under EOD, animals were also trained by using a treadmill for another 6 weeks and then analyzed for physical activity. Both, EOD and endurance exercise increased the resistance of animals to extenuating activity and improved motor coordination. Among the groups that showed the highest performance, AL and EOD trained animals, ALT and EODT respectively, only the EODT group was able to increase glucose and triglycerides levels in plasma after extenuating exercise. No high effects on mitochondrial respiratory chain activities or protein levels neither on coenzyme Q levels were found in gastrocnemius muscle. However, exercise and EOD did increase ß-oxidation activity in this muscle accompanied by increased CD36 levels in animals fed under EOD and by changes in shape and localization of mitochondria in muscle fibers. Furthermore, EOD and training decreased muscle damage after strenuous exercise. EOD also reduced the levels of lipid peroxidation in muscle. Our results indicate that EOD improves muscle performance and resistance by increasing lipid catabolism in muscle mitochondria at the same time that prevents lipid peroxidation and muscle damage.

Histone H1 poly[ADP]-ribosylation regulates the chromatin alterations required for learning consolidation.

Memory formation requires changes in gene expression, which are regulated by the activation of transcription factors and by changes in epigenetic factors. Poly[ADP]-ribosylation of nuclear proteins has been postulated as a chromatin modification involved in memory consolidation, although the mechanisms involved are not well characterized. Here we demonstrate that poly[ADP]-ribose polymerase 1 (PARP-1) activity and the poly[ADP]-ribosylation of proteins over a specific time course is required for the changes in synaptic plasticity related to memory stabilization in mice. At the molecular level, histone H1 poly[ADP]-ribosylation was evident in the hippocampus after the acquisition period, and it was selectively released in a PARP-1-dependent manner at the promoters of cAMP response element-binding protein and nuclear factor-κB dependent genes associated with learning and memory. These findings suggest that histone H1 poly[ADP]-ribosylation, and its loss at specific loci, is an epigenetic mechanism involved in the reprogramming of neuronal gene expression required for memory consolidation.

From learning to forgetting: behavioral, circuitry, and molecular properties define the different functional states of the recognition memory trace.

Neuropsychological analyses of amnesic patients, as well as lesion experiments, indicate that the temporal lobe is essential for the encoding, storage, and expression of object recognition memory (ORM). However, temporal lobe structures directly involved in the consolidation and reconsolidation of these memories are not yet well-defined. We report here that systemic administration of a protein synthesis inhibitor before or up to 4 h after training or reactivation sessions impairs consolidation and reconsolidation of ORM, without affecting short-term memory. We have also observed that ORM reconsolidation is sensitive to protein synthesis inhibition, independently of the ORM trace age. Using bdnf and egr-1 gene expression analysis, we defined temporal lobe areas related to consolidation and reconsolidation of ORM. Training and reactivation 21 days after ORM acquisition sessions provoked changes in bdnf mRNA in somatosensory, perirhinal, and hippocampal cortices. Reactivation 2 days after the training session elicited changes in bdnf and egr-1 mRNA in entorhinal and prefrontal cortices, while reactivation 9 days post-training provoked an increase in egr-1 transcription in somatosensory and entorhinal cortices. The differences in activated circuits and in the capacity to recall the memory trace after 9 or 21 days post-training suggest that memory trace suffers functional changes in this period of time. All these results indicate that the functional state of the recognition memory trace, from acquisition to forgetting, can be specifically defined by behavioral, circuitry, and molecular properties.