Endosomal dysfunction impacts extracellular vesicle release: Central role in Aß pathology.

Alzheimer's Disease (AD) is characterized by progressive loss of cognitive abilities; senile plaques represent the major histopathological findings. Amyloid precursor protein (APP) processing machinery, and its product amyloid-beta (Aß) peptide, have been found in extracellular vesicles (EVs), specifically exosomes, which allows for Aß peptide aggregation and subsequent senile plaques deposition. We review the APP processing imbalance in EVs, autophagic and endosomal pathways in AD. Increased intraluminal vesicle (ILV) production and exosome release appear to counteract the endosomal dysfunction of APP processing; however, this process results in elevated amyloidogenic processing of APP and augmented senile plaque deposition. Several players related to APP processing and dysfunctional endosomal-lysosomal-exosomal (and other EVs) pathway are described, and the interconnected systems are discussed. The components Arc, p75, Rab11 and retromer complex emerge as candidates for key convergent mechanisms that lead to increased EVs loaded with APP machinery and Aß levels, in atrophy and damage of basal forebrain cholinergic neurons in AD.

Neonatal morphine administration leads to changes in hippocampal BDNF levels and antioxidant enzyme activity in the adult life of rats.

It is know that repeated exposure to opiates impairs spatial learning and memory and that the hippocampus has important neuromodulatory effects after drug exposure and withdrawal symptoms. Thus, the aim of this investigation was to assess hippocampal levels of BDNF, oxidative stress markers associated with cell viability, and TNF-α in the short, medium and long term after repeated morphine treatment in early life. Newborn male Wistar rats received subcutaneous injections of morphine (morphine group) or saline (control group), 5 µg in the mid-scapular area, starting on postnatal day 8 (P8), once daily for 7 days, and neurochemical parameters were assessed in the hippocampus on postnatal days 16 (P16), 30 (P30), and 60 (P60). For the first time, we observed that morphine treatment in early life modulates BDNF levels in the medium and long term and also modulates superoxide dismutase activity in the long term. In addition, it was observed effect of treatment and age in TNF-α levels, and no effects in lactate dehydrogenase levels, or cell viability. These findings show that repeated morphine treatment in the neonatal period can lead to long-lasting neurochemical changes in the hippocampus of male rats, and indicate the importance of cellular and intracellular adaptations in the hippocampus after early-life opioid exposure to tolerance, withdrawal and addiction.

Effect of different exercise protocols on histone acetyltransferases and histone deacetylases activities in rat hippocampus.

Regular and moderate exercise has been considered an interesting neuroprotective strategy. Although the mechanisms by which physical exercise alters brain function are not clear, it appears that neuroprotective properties of exercise could be related to chromatin remodeling, specifically the induction of histone acetylation through modulation of histone deacetylases (HDAC) and histone acetyltransferases (HAT) activities. The aim of the present work was to investigate the effect of exercise on HDAC and HAT activities in rat whole hippocampus at different times after treadmill. Adult male Wistar rats were assigned to non-exercised (sedentary) and exercised groups on different protocols: a single session of treadmill exercise (running for 20 min) and a chronic treadmill protocol (running once daily for 20 min, for 2 weeks). The effects of exercise on HDAC and HAT activities were measured immediately, 1 h and 18 h after the single session or the last training session of chronic treadmill exercise using specific assay kits. The single session of treadmill exercise reduced HDAC activity, increased HAT activity and increased the HAT/HDAC balance in rat hippocampus immediately and 1 h after exercise, an indicative of histone hyperacetylation status. The acetylation balance was also influenced by the circadian rhythm, since the HAT/HDAC ratio was significantly decreased in the early morning in all groups when compared to the afternoon. These data support the hypothesis that exercise neuroprotective effects may be related, at least in part, to acetylation levels through modulation of HAT and HDAC activities. We also demonstrated circadian changes in the HAT and HDAC activities and, consequently, in the acetylation levels.

The modified 2VO ischemia protocol causes cognitive impairment similar to that induced by the standard method, but with a better survival rate

Permanent bilateral occlusion of the common carotid arteries (2VO) in the rat has been established as a valid experimental model to investigate the effects of chronic cerebral hypoperfusion on cognitive function and neurodegenerative processes. Our aim was to compare the cognitive and morphological outcomes following the standard 2VO procedure, in which there is concomitant artery ligation, with those of a modified protocol, with a 1-week interval between artery occlusions to avoid an abrupt reduction of cerebral blood flow, as assessed by animal performance in the water maze and damage extension to the hippocampus and striatum. Male Wistar rats (N = 47) aged 3 months were subjected to chronic hypoperfusion by permanent bilateral ligation of the common carotid arteries using either the standard or the modified protocol, with the right carotid being the first to be occluded. Three months after the surgical procedure, rat performance in the water maze was assessed to investigate long-term effects on spatial learning and memory and their brains were processed in order to estimate hippocampal volume and striatal area. Both groups of hypoperfused rats showed deficits in reference (F(8,172) = 7.0951, P < 0.00001) and working spatial memory [2nd (F(2,44) = 7.6884, P < 0.001), 3rd (F(2,44) = 21.481, P < 0.00001) and 4th trials (F(2,44) = 28.620, P < 0.0001)]; however, no evidence of tissue atrophy was found in the brain structures studied. Despite similar behavioral and morphological outcomes, the rats submitted to the modified protocol showed a significant increase in survival rate, during the 3 months of the experiment (P < 0.02).

The modified 2VO ischemia protocol causes cognitive impairment similar to that induced by the standard method, but with a better survival rate.

Permanent bilateral occlusion of the common carotid arteries (2VO) in the rat has been established as a valid experimental model to investigate the effects of chronic cerebral hypoperfusion on cognitive function and neurodegenerative processes. Our aim was to compare the cognitive and morphological outcomes following the standard 2VO procedure, in which there is concomitant artery ligation, with those of a modified protocol, with a 1-week interval between artery occlusions to avoid an abrupt reduction of cerebral blood flow, as assessed by animal performance in the water maze and damage extension to the hippocampus and striatum. Male Wistar rats (N = 47) aged 3 months were subjected to chronic hypoperfusion by permanent bilateral ligation of the common carotid arteries using either the standard or the modified protocol, with the right carotid being the first to be occluded. Three months after the surgical procedure, rat performance in the water maze was assessed to investigate long-term effects on spatial learning and memory and their brains were processed in order to estimate hippocampal volume and striatal area. Both groups of hypoperfused rats showed deficits in reference (F(8,172) = 7.0951, P < 0.00001) and working spatial memory [2nd (F(2,44) = 7.6884, P < 0.001), 3rd (F(2,44) = 21.481, P < 0.00001) and 4th trials (F(2,44) = 28.620, P < 0.0001)]; however, no evidence of tissue atrophy was found in the brain structures studied. Despite similar behavioral and morphological outcomes, the rats submitted to the modified protocol showed a significant increase in survival rate, during the 3 months of the experiment (P < 0.02).

Highly palatable diet consumption increases protein oxidation in rat frontal cortex and anxiety-like behavior.

Obesity is frequently associated with consumption of high amounts of sugar and/or fat. Studies have demonstrated a high prevalence of overweight and obesity associated or not with increase rates of psychiatry disorders, in particular mood and anxiety disorders. Recent works have demonstrated an association between specific genes involved in oxidative stress metabolism and anxiety-like behavior. The aim of this study was to investigate the effect of a highly palatable diet enriched with sucrose in body fat mass composition, anxiety behavior and brain oxidative status. Twenty male Wistar rats received two different diets during four months: standard chow (SC) and highly palatable (HP). Metabolic parameters, behavioral tests and oxidative stress status were evaluated. Body fat mass, insulin sensitivity and glucose tolerance were altered in the HP group (p<0.01). The same group spends less time in light compartment and had a lower risk assessment behavior (p<0.05) but no differences were observed in the open field test habituation (p>0.05). Protein degradation, DCF and TBARS levels were not different in the hippocampus between groups; however, there were higher levels of protein degration in frontal cortex of HP groups (p<0.05), although DCF and TBARS levels don't differ from the SC group (p>0.05). In conclusion, our data suggest that the consumption of HP diet leads to an obese phenotype, increases protein oxidation in frontal cortex and appears to induce anxiety-like behavior in rats.

Antioxidant activities of Ptychopetalum olacoides ("muirapuama") in mice brain.

Ptychopetalum olacoides (PO) roots are used by Amazonian peoples to prepare traditional remedies for treating various central nervous system conditions in which free radicals are likely to be implicated. Following the identification of PO ethanol extract (POEE) free-radical scavenging properties in vitro, the aim of this study was to verify the in vivo antioxidant effect of POEE. Aging mice (14 months) were treated (i.p.) with saline, DMSO (20%) or POEE (100mg/kg body wt.), and the hippocampi, cerebral cortex, striata, hypothalamus and cerebellum dissected out 60 min later to measure antioxidant enzyme activities, free-radical production and damage to macromolecules. POEE administration reduced free-radical production in the hypothalamus, lead to significant decrease in lipid peroxidation in the cerebral cortex, striatum and hypothalamus, as well as in the carbonyl content in cerebellum and striatum. In terms of antioxidant enzymes, catalase activity was increased in the cortex, striatum, cerebellum and hippocampus, while glutathione peroxidase activity was increased in the hippocampus. This study suggests that POEE contains compounds able to improve the cellular antioxidant network efficacy in the brain, ultimately reducing the damage caused by oxidative stress.

Prevalência de nódulos de tireóide detectados por ecografia em mulheres após os 40 anos / Prevalence of thyroid nodules in 40 years-old or old women

Nódulos de tireóide säo uma condiçäo clínica comum e em seu diagnóstico diferencial inclui-se o câncer de tireóide. Como o câncer de tireóide é raro, é importante conhecer a prevalência de nódulos de tireóide em grupos fortemente pre-dispostos para dimensionar seu impacto e adequar estratégias diagnósticas. OBJETIVOS: O objetivo deste estudo foi verificar a prevalência de nódulos de tireóide diagnosticados por ecografia em mulheres na maturidade. MÉTODOS: Entre agosto de 1996 e dezembro de 1997 foram avaliadas, de forma consecutiva, pacientes do sexo feminino com idade de 40 anos ou mais que realizavam ecografia no Serviço de Radiologia do HCPA...