Defects in neuronal activity of the entorhinal cortex (EC) are suspected to underlie the symptoms of Alzheimer's disease (AD). Whereas neuroprotective effects of docosahexaenoic acid (DHA) have been ...described, the effects of DHA on the physiology of EC neurons remain unexplored in animal models of AD. Here, we show that DHA consumption improved object recognition (↑12%), preventing deficits observed in old 3xTg-AD mice (↓12%). Moreover, 3xTg-AD mice displayed seizure-like akinetic episodes, not detected in NonTg littermates and partly prevented by DHA (↓50%). Patch-clamp recording revealed that 3xTg-AD EC neurons displayed (i) loss of cell capacitance (CC), suggesting reduced membrane surface area; (ii) increase of firing rate versus injected current (F-I) curve associated with modified action potentials, and (iii) overactivation of glutamatergic synapses, without changes in synaptophysin levels. DHA consumption increased CC (↑12%) and decreased F-I slopes (↓21%), thereby preventing the opposite alterations observed in 3xTg-AD mice. Our results indicate that cognitive performance and basic physiology of EC neurons depend on DHA intake in a mouse model of AD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Because sirtuins may increase the life span through regulation of cellular metabolism, we compared the ...concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (messenger RNA mRNA, −29%; protein, −45%) in the parietal cortex of AD patients, but not in the cerebellum. Further analyses in a second cohort of 36 subjects confirmed that cortical SIRT1 was decreased in AD but not in individuals with mild cognitive impairment. SIRT1 mRNA and its translated protein correlated negatively with the duration of symptoms (mRNA, r = −0.367; protein, r = −0.326) and the accumulation of paired helical filament tau (mRNA, r = −0.230; protein, r = −0.119), but weakly with insoluble amyloid-β 42 (mRNA, r = −0.090; protein, r = −0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r = +0.09, p = 0.049). In contrast, cortical SIRT1 levels remained unchanged in a triple-transgenic animal model of AD. Collectively, our results indicate that loss of SIRT1 is closely associated with the accumulation of amyloid-β and tau in the cerebral cortex of persons with AD.
► 3xTg-AD mutants were deficient in reversal, object recognition, and avoidance learning. ► The mutants also showed hypoactivity in two open-field tests. ► The mutants did not differ from controls in ...anxiety and motor coordination. ► The mutants did not differ in nest-building and reflexes. ► Their hypoactivity is akin to Alzheimer-related apathy.
3xTg-AD mutant mice are characterized by parenchymal Aβ plaques and neurofibrillary tangles resembling those found in patients with Alzheimer's disease. The mutants were compared with non-transgenic controls in sensorimotor and learning tests. 3xTg-AD mutants were deficient in T-maze reversal, object recognition, and passive avoidance learning. In addition, the mutants showed hypoactivity in two open-field tests, fewer fecal boli in an observation jar, and reduced enclosed arm entries and head-dipping in the elevated plus-maze. On the contrary, the mutants did not differ from controls in pain thresholds, nest-building, and various reflexes determined by the SHIRPA primary screen and were even better on the rotorod test of motor coordination.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. ...NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)(sw) (Swedish double mutation APP695(sw), K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Consumption of fish has been shown to reduce risk of coronary heart disease and, possibly, of ischemic stroke. Because docosahexaenoic acid (DHA) is the most likely neuroactive component within fish ...oil, we hypothesized that exposing mice to a DHA-enriched diet may reduce inflammation and protect neurons against ischemic injury.
To visualize the effects of DHA on neuroinflammation after stroke, TLR2-fluc-GFP transgenic mice were exposed to either a control diet, a diet depleted in n-3 polyunsaturated fatty acid, or a diet enriched in DHA during 3 months. Real-time biophotonic/bioluminescence imaging of the TLR2 response was performed before and after middle cerebral artery occlusion, whereas cytokines concentrations and stroke area analyses were performed at 3 and 7 days after middle cerebral artery occlusion, respectively.
We show that a 3-month DHA treatment prevented microglial activation after ischemic injury, reduced the ischemic lesion size, and increased levels of the antiapoptotic molecule Bcl-2 in the brain. Additional analysis revealed a significant decrease in the levels of COX2 and IL-1β, but not in other proinflammatory cytokines. Importantly, long-term DHA supplementation significantly changed the n-3:n-6 polyunsaturated fatty acid ratio in the brain.
Collectively, these data indicate that diet-induced accumulation of DHA in the brain protects against postischemic inflammation and injury. Because DHA is widely available at low cost and has an excellent safety profile, our data suggest that increased DHA intake may provide protection against acute immune response/brain damage in ischemic stroke.
Abstract
The aim of this study was to evaluate the effect of formulations of vitamin K, organic acids, essential oils and plant hydroalcoholic extracts as anticoccidial alternatives in broilers. A ...34-day cage trial with 10 replicates of 12 birds/cage was conducted. Male broilers (Ross 308) were randomly assigned to: 1) non-infected (NI); 2) Eimeria-infected (EI); 3) EI+decoquinate/zoalene shuttle program (DZ); 4) EI+2 kg/t Nutri-Gro® feed additive; 5) 3 L/1000 L Technocok® in drinking water from d14 to d20. The formulations were made by Synergie Eurobec International Ltd and contain 7.0 and 7.5 g/kg vitamin K. Eimeria infection was induced by an oral administration at d14 of 2x105 sporulated oocysts of mixed Eimeria species from field isolates. Data were analyzed by a mixed model including treatment and barn section as fixed and random effects, respectively, and by Kruskal-Wallis tests. As expected, the coccidian challenge (EI) reduced growth performances, increased total excreted oocyst counts (6.0 vs 3.0 log10, P < 0.0001) and E. acervulina (0.79 vs 0.21, P=0.0022) and E. tenella (2.04 vs 0.17, P < 0.0001) intestinal lesion scores (ILS) 6 days post infection (dpi, d20), compared to NI, whereas DZ palliated these infection impacts. The two formulation treatments increased d20 body weight (BW), compared to EI (0.980 and 0.939 vs 0.908 kg, P < 0.01), without improving the feed conversion ratio (FCR). The 2 kg/t Nutri-Gro® formulation increased (2.69 vs 2.61 kg, P=0.0486) and the Technocok® showed a trend to improve (2.68 vs 2.61 kg, P=0.1015) d34 BW, compared to EI birds. However, the formulations did not affect the oocyst excretion nor the ILS at 6 dpi (P>0.05). Overall, the additives showed beneficial effects on growth performance in a Eimeria-challenged broilers. These supplements may be involved in a strategy aimed at reducing the use of anticoccidials in broiler production.
Abstract C. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). ...Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TDP-43 toxicity. Consequently here we investigated how MB might exert its neuroprotective properties and found that it acts through reduction of the endoplasmic reticulum (ER) stress response. We tested other compounds known to be active in the ER unfolded protein response in worms and zebrafish expressing mutant human TDP-43 (mTDP-43). We identified three compounds: salubrinal, guanabenz and a new structurally related compound phenazine, which also reduced paralysis, neurodegeneration and oxidative stress in our mTDP-43 models. Using C. elegans genetics, we showed that all four compounds act as potent suppressors of mTDP-43 toxicity through reduction of the ER stress response. Interestingly, these compounds operate through different branches of the ER unfolded protein pathway to achieve a common neuroprotective action. Our results indicate that protein-folding homeostasis in the ER is an important target for therapeutic development in ALS and other TDP-43-related neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This study evaluated effects of feeding low-bush wild blueberry (LBP) and organic American cranberry (CRP) pomaces without or with multienzyme supplement (ENZ) on growth performance, organ weight and ...plasma metabolites in broiler chickens. Nonenzyme-fed (no-ENZ: n = 1,575) and enzyme-fed (ENZ: n = 1,575) day-old male Cobb500 broilers were placed in floor pens (45 chicks/pen) and allocated to five corn-soybean meal-based diets: a basal diet supplemented with either bacitracin methylene disalicylate (BMD, 55 mg/kg), 0.5 or 1% of CRP or LBP in a 2 × 5 factorial design for 35-day experiment. Body weight (BW), feed intake (FI) and mortality were recorded whereas BW gain (BWG) and feed conversion ratio (FCR) were calculated. Birds were sampled at days 21 and 35 for organ weights and plasma metabolites. There were no interactions between diet and ENZ on any parameter (P > 0.05) and no effect of ENZ on overall (d 0–35) growth performance and organ weights (P > 0.05). Birds fed BMD were heavier (P < 0.05) at d 35 and had better overall FCR than berry-supplemented birds. Birds fed 1% LBP had poor FCR than birds fed 0.5% CRP. Birds fed LBP exhibited heavier liver (P < 0.05) than birds fed BMD or 1% CRP. The highest plasma concentrations of aspartate transaminase (AST), creatine kinase (CK) at d 28 and gamma-glutamyl transferase (GGT) at d 35 were found in ENZ-fed birds (P < 0.05). At d 28, birds fed 0.5% LBP showed higher plasma AST and CK concentrations (P < 0.05). However, CRP feeding resulted in a lower plasma CK level compared with BMD feeding (P < 0.05). The lowest cholesterol level was detected in 1% CRP-fed birds. In conclusion, this study showed no ENZ effects to potentiate berry pomaces on the overall growth performance of broilers (P < 0.05. However, plasma profiles revealed the potential of ENZ to modulate the metabolism of pomace-fed broilers. LBP increased BW during the starter phase, while CRP increased BW during the grower phase.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
In recent years, for economical purposes and to improve well-being conditions of cows, several dairy producers have adopted litter made from recycled manure solids (RMS). However, its use ...raises several safety issues, particularly with respect to mastitis and other infections. We previously observed cases of mastitis caused by K. pneumoniae and K. variicola, and two deadly infections from C. perfringens from cows on RMS. A herd of Holstein cows, distributed in two barns of about 40 lactating cows, was used. RMS was used in one barn, and wood-chip litter (WCL), in the other. RMS was generated by roller presses separation followed by conditioning at 55°C for 24h. Clean and soiled (used) RMS and WCL samples were collected for 15 months. Similarly, material samples before conditioning were also collected, and all samples were analyzed by viability-qPCR. Milk samples from cows with mastitis and somatic cell count data (SCC) were analyzed. Total and living contents of K. pneumoniae, K. variicola, C. perfringens and Klebsiella spp. were higher in the RMS than the WCL (+1.6–4.2 log10, P < 0.05). Composting 24h at 55°C did not affect total and live levels of C. perfringens, K. pneumoniae, and even increased total and live levels of K. variicola (+0.9 log10, P < 0.05). A seasonal effect or the number of cycles recycling the RMS decreased levels of K. pneumoniae in winter. Overall, RMS had no significant effect on SCC, but increased mastitis incidence (+39%, P < 0.05), compared to WCL. Milk analysis revealed that higher levels of K. pneumoniae found in RMS could contribute to the increase in mastitis cases caused by this pathogen. Data reported from this study are not favorable to the use of an RMS conditioned for 24h at 55°C with dairy cows, apropos the microbiological aspect; however, these results must be confirmed by other studies.
In recent years, for economical purposes and to improve well-being conditions of cows, several dairy producers have adopted litter made from recycled manure solids (RMS). However, its use raises ...several safety issues, particularly with respect to mastitis and other infections. We previously observed cases of mastitis caused by K. pneumoniae and K. variicola, and two deadly infections from C. perfringens from cows on RMS. A herd of Holstein cows, distributed in two barns of about 40 lactating cows, was used. RMS was used in one barn, and wood-chip litter (WCL), in the other. RMS was generated by roller presses separation followed by conditioning at 55°C for 24h. Clean and soiled (used) RMS and WCL samples were collected for 15 months. Similarly, material samples before conditioning were also collected, and all samples were analyzed by viability-qPCR. Milk samples from cows with mastitis and somatic cell count data (SCC) were analyzed. Total and living contents of K. pneumoniae, K. variicola, C. perfringens and Klebsiella spp. were higher in the RMS than the WCL (+1.6-4.2 log10, P < 0.05). Composting 24h at 55°C did not affect total and live levels of C. perfringens, K. pneumoniae, and even increased total and live levels of K. variicola (+0.9 log10, P < 0.05). A seasonal effect or the number of cycles recycling the RMS decreased levels of K. pneumoniae in winter. Overall, RMS had no significant effect on SCC, but increased mastitis incidence (+39%, P < 0.05), compared to WCL. Milk analysis revealed that higher levels of K. pneumoniae found in RMS could contribute to the increase in mastitis cases caused by this pathogen. Data reported from this study are not favorable to the use of an RMS conditioned for 24h at 55°C with dairy cows, apropos the microbiological aspect; however, these results must be confirmed by other studies.
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