Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is widely used in rodent models to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology. STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-ß (Aß) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might have facilitated a direct neurotoxic effect of STZ in older mice. Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.

Effects of summer treatments against Varroa destructor on viral load and colony performance of Apis mellifera colonies in Eastern Canada.

Despite the use of various integrated pest management strategies to control the honey bee mite, Varroa destructor, varroosis remains the most important threat to honey bee colony health in many countries. In Canada, ineffective varroa control is linked to high winter colony losses and new treatment options, such as a summer treatment, are greatly needed. In this study, a total of 135 colonies located in 6 apiaries were submitted to one of these 3 varroa treatment strategies: (i) an Apivar® fall treatment followed by an oxalic acid (OA) treatment by dripping method; (ii) same as in (i) with a summer treatment consisting of formic acid (Formic Pro™); and (iii) same as in (i) with a summer treatment consisting of slow-release OA/glycerin pads (total of 27 g of OA/colony). Treatment efficacy and their effects on colony performance, mortality, varroa population, and the abundance of 6 viruses (acute bee paralysis virus [ABPV], black queen cell virus [BQCV], deformed wing virus variant A [DWV-A], deformed wing virus variant B [DWV-B], Israeli acute paralysis virus [IAPV], and Kashmir bee virus [KBV]) were assessed. We show that a strategy with a Formic Pro summer treatment tended to reduce the varroa infestation rate to below the economic fall threshold of 15 daily varroa drop, which reduced colony mortality significantly but did not reduce the prevalence or viral load of the 6 tested viruses at the colony level. A strategy with glycerin/OA pads reduced hive weight gain and the varroa infestation rate, but not below the fall threshold. A high prevalence of DWV-B was measured in all groups, which could be related to colony mortality.

Honeybees as a biomonitoring species to assess environmental airborne pollution in different socioeconomic city districts.

Honeybees have been used in Europe as environmental bioindicators for heavy metals and polycyclic aromatic hydrocarbons (PAHs). However, their potential has been little explored in North America, especially between environments which have similar pollution levels. Many urban residents and stakeholders are concerned with air quality, mainly in regard to gradients of exposure to industrial pollution between deprived and privileged subpopulation. Thus, the aim of this study was to evaluate the use of honeybees as bioindicators to assess exposure to heavy metals and PAHs in Québec City, Canada, in different socioeconomic districts of Quebec City (deprivation index). Honeybees were sampled over a 5-month period (May to September) at six locations distributed in two urban areas that are distinct geomorphologically and socioeconomically (lower town socio-economically deprived and upper town socioeconomically privileged) and two control rural locations. Six PAHs were analyzed by ultra-performance liquid chromatography (UPLC), while four heavy metals were analyzed by inductively coupled plasma mass spectrometry. Arsenic was the only measured pollutant that showed a significant gradient of exposure between rural and urban environments, but also between the two urban areas. Furthermore, we were able to detect significant differences at certain sampling times for heavy metals and PAHs. Overall, the results show that honeybees are sensitive enough to detect differences between the differential urban environments of a city presumed to have similar pollution levels and therefore could be used when potential socio-environmental inequalities are present.

Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.

Characterization of a 3xTg-AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background.

No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aß plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aß40 and Aß42 concentrations (Aß40, +85%; Aß42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aß42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.

Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease.

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.

Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice.

Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.

Is there a right time for dairy Alpine goat kid weaning: How does the weaning age of dairy Alpine goat kids affect their growth and behavior?

In dairy goat kids, weaning is often associated with poor growth leading to a decline in welfare and performance; however, little is known about optimal weaning practices. This study aimed to determine the optimal weaning age for dairy goat kids to maximize outcome measures of welfare related to growth, feed intake, and behavior. Thirty-six newborn female Alpine kids were blocked by weight and birth date, paired with a similar male companion and randomly allocated to one of the three weaning age treatments: 6 (6W), 8 (8W), and 10 wk (10W). Kids had ad libitum access to acidified milk replacer refilled twice daily, concentrates, hay, and water. Milk consumption was measured daily, and concentrate consumption, weekly. Ten behaviors were live observed on days -8, -4, 0, 6, and 12 relative to weaning (i.e., weaning day = 0). Kruskal-Wallis tests were used to assess differences from baseline between the 6W, 8W, and 10W treatments. Post hoc analysis using the Dwass, Steel, Critchlow-Fligner (DSCF) multiple comparison analysis was used to evaluate pairwise treatment differences based on two-sample Wilcoxon comparisons. Kids weaned at 10 wk had the greatest increase compared to baseline in concentrate consumption (P = 0.0160), and greatest decrease compared to baseline in vocalization (P = 0.0008) while both 8- and 10- wk kid's groups had the greatest increase compared to baseline in self-grooming time (P < 0.0001), and cross-sucking time (P = 0.0006). Kids weaned at 6 wk of age were found to have the smallest increase compared to baseline in concentrate consumption (P = 0.0160) and self-grooming time (P < 0.0001), and the greatest increase compared to baseline in allogrooming time (P = 0.0032) and in redirected behaviors aimed towards the environment (biting and licking time [P = 0.0173]; displacement at the nipple frequency [P = 0.0236]). No negative impact of weaning on growth of either group was identified. Overall, our results tend towards a higher degree of discomfort behaviors (allogrooming, biting/licking, displacement, and vocalizations) in kids weaned earlier compared to later weaning, while kids weaned later showed higher levels of positive behaviors (lying time and self-grooming).

In dairy goat kids, there is limited literature available on weaning management practices, despite this period being one of the most stressful events for kids and being associated with measures of poor welfare. This study aimed to compare weaning of dairy goat kids at 6-, 8-, and 10-wk of age to maximize outcome measures of welfare related to growth, feed intake, and behavior. Kids weaned at 10 wk of age had the greatest increase in concentrate consumption and decrease in vocalization. Both 8- and 10-wk kids had the greatest increase in self-grooming and cross-sucking. Kids weaned at 6-wk of age had the smallest increase in concentrate consumption, greatest decrease in self-grooming, and greatest increase in allogrooming and redirected behaviors aimed towards the environment. No negative impact of weaning on growth was identified. Our results showed a higher degree of discomfort behaviors in kids weaned earlier compared to later weaning at 8- or 10-wk. Despite similar levels of discomfort behaviors for kids weaned at later ages, vocalization difference was greatest for kids weaned at 8 wk of age. Kids weaned at later ages seem to cope better with the transition to solid feed compared to kids weaned at an early age.

Methods for Biochemical Isolation of Insoluble Tau in Rodent Models of Tauopathies.

The intracellular accumulation of microtubule-associated protein tau is a characteristic feature of tauopathies, a group of neurodegenerative diseases including Alzheimer's disease. Formation of insoluble tau aggregates is initiated by the abnormal hyperphosphorylation and oligomerization of tau. Over the past decades, multiple transgenic rodent models mimicking tauopathies have been develop, showcasing this neuropathological hallmark. The biochemical analysis of insoluble tau in these models has served as a valuable tool to understand the progression of tau-related pathology. In this chapter, we provide a comprehensive review of the two primary methods for isolating insoluble tau, namely, sarkosyl and formic acid extraction (and their variants), which are employed for biochemical analysis in transgenic mouse models of tauopathy. We also analyze the strengths and limitations of these methods.

Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo.

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.

Growth performance, organ weight, and plasma metabolites in broiler chickens fed corn-soybean meal diet containing berry pomaces and fed without or with multienzymes supplement.

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.

A Changing Landscape for Lifelong Learning in Health Globally.

On 25 July 2022, the Continuing Professional Development (CPD) Special Interest Group of the Association for Medical Education in Europe came together to open up discussions during a live webinar on 'Exploring the Evolution of CPD'. The objective was to bring together global medical educators to consider perspectives of CPD from the role of global lifelong learners, the role of educators and the role of education providers and health regulators. The landscape of CPD is evolving, and the roles of each key player must include specific actions for facilitated change. Delivering competency outcomes-based learning, fit for purpose, to lifelong learners in health will require (1) learner agency, (2) leadership from educators and (3) providers of lifelong learning to come together to improve delivery of CPD that leads to meaningful change in practice care delivery.

Dietary intake of unsaturated fatty acids modulates physiological properties of entorhinal cortex neurons in mice.

Dietary lipids modify brain fatty acid profile, but evidence of their direct effect on neuronal function is sparse. The enthorinal cortex (EC) neurons connecting to the hippocampus play a critical role in learning and memory. Here, we have exposed mice to diets based on canola:soybean oils (40 : 10, g/kg) or safflower : corn oils (25 : 25, g/kg) to investigate the relationship between the lipid profile of brain fatty acids and the intrinsic properties of EC neurons. Consumption of canola : soybean oil-enriched diet led to the increase of the monounsaturated fatty acid oleic acid and to a decrease of arachidonic acid in ethanolamine glycerophospholipids of the white matter. We also found an important rise in docosahexaenoic acid (DHA) within ethanolamine glycerophospholipids and phosphatidylserine of gray matter. The canola:soybean oil treatment led to a shorter duration of action potential (-21%), a reduction in the duration of postsynaptic response (-21%) and increased firing activity (+43%). Data from additional experiments with animals fed DHA alone or DHA with canola oil suggested that dietary monounsaturated fatty acid may have contributed to these effects on EC neuron physiology. Since neuronal function within the enthorhinal-hippocampal loop is critical to learning and memory processes, the present data may provide a functional basis for the beneficial cognitive effects of canola oil-based diets.

Chronic dietary intake of α-linolenic acid does not replicate the effects of DHA on passive properties of entorhinal cortex neurons.

n-3 PUFA are receiving growing attention for their therapeutic potential in central nervous system (CNS) disorders. We have recently shown that long-term treatment with DHA alters the physiology of entorhinal cortex (EC) neurons. In the present study, we investigated by patch-clamp the effect of another major dietary n-3 PUFA, α-linolenic acid (LNA), on the intrinsic properties of EC neurons. Mice were chronically exposed to isoenergetic diets deficient in n-3 PUFA or enriched in either DHA or LNA on an equimolar basis. GC analyses revealed an increase in DHA (34%) and a decrease in arachidonic acid (AA, - 23%) in brain fatty acid concentrations after consumption of the DHA-enriched diet. Dietary intake of LNA similarly affected brain fatty acid profiles, but at a lower magnitude (DHA: 23%, AA: - 13%). Compared to the n-3 PUFA-deficient diet, consumption of DHA, but not LNA, induced membrane hyperpolarisation ( -60 to -70 mV), increased cellular capacitance (32%) and spontaneous excitatory postsynaptic current frequency (50%). We propose that the inefficiency of LNA to modulate cellular capacitance was related to its inability to increase the brain DHA:AA ratio over the threshold necessary to up-regulate syntaxin-3 (46%) and translocate drebrin (40% membrane:cytosol ratio). In summary, our present study shows that the increase in brain DHA content following chronic administration of LNA was not sufficient to alter the passive and synaptic properties of EC neurons, compared to direct dietary intake of DHA. These diverging results have important implications for the therapeutic use of n-3 PUFA in CNS disease, favouring the use of preformed DHA.

Adult Gastroenterology Trainees' Experience of Receiving Feedback on Their Performance of Endoscopy in the Workplace.

BACKGROUND: Competency-based gastrointestinal endoscopy training is concerned with outcomes of the learning experience. Feedback allows for trainees to achieve the expected outcomes. However, little is known about trainees' experience of receiving feedback. Gaining understanding of their experience could help improve feedback practices. The study was conducted to explore what it means for adult gastroenterology trainees to receive feedback on their performance of endoscopy in the workplace. METHODS: An interpretative phenomenological approach was used. Individual semi-structured interviews were conducted with six trainees from three Canadian adult gastroenterology residency programs. Interviews were audio-recorded and transcribed verbatim for analysis. Analysis was conducted to identify the phenomenological themes across participants' accounts of lived experience to provide an insight into the meaning of experiencing the studied phenomenon. FINDINGS: Three phenomenological themes of experience were identified: taking pauses, negotiating understandings and accepting asymmetry. Taking pauses allowed for participants to receive feedback on their performance of endoscopy. Participants needed to negotiate attending gastroenterologists' different understandings of gastrointestinal endoscopy while carrying their own whenever feedback was provided. They had to accept the asymmetry between the roles of care provider and learner as well. DISCUSSION: The study has captured the uniqueness and the complexity of the lived experience of receiving feedback on the performance of endoscopy in the workplace from the perspective of study participants. The gained understanding of this experience has enabled the authors to suggest how attending gastroenterologists' feedback practices may be improved.

Accumulation of dietary docosahexaenoic acid in the brain attenuates acute immune response and development of postischemic neuronal damage.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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-1ß, 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. CONCLUSIONS: 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.

Effects of Vaccination Against Coccidiosis on Gut Microbiota and Immunity in Broiler Fed Bacitracin and Berry Pomace.

Feeding practices have been found to influence gut microbiota which play a major role in immunity of poultry. In the present study, changes in cecal microbiota and humoral responses resulting in the 55 ppm bacitracin (BACI), 1% each of cranberry (CP1) and wild blueberry (BP1) pomace alone or in combination (CP+BP) feeding in broiler Cobb 500 vaccinated or not against coccidiosis were investigated. In the non-vaccinated group, no significant treatment effects were observed on performance parameters. Vaccination significantly affected bird's performance parameters particularly during the growing phase from 10 to 20 days of age. In general, the prevalence of coccidiosis and necrotic enteritis (NE) was reduced by vaccination (P < 0.05). BACI-treated birds showed low intestinal lesion scores, and both CP1 and BP1 feed supplementations reduced Eimeria acervulina and Clostridium perfringens incidences similar to BACI. Vaccination induced change in serum enzymes, minerals, and lipid levels in 21-day old birds while, levels of triglyceride (TRIG) and non-esterified fatty acids (NEFA) were higher (P < 0.05) in CP1 treated non-vaccinated group than in the control. The levels of NEFA were lower in BACI- and CP1-fed birds than in the control in non-vaccinated day 28 old birds. The highest levels of all estimated three immunoglobulins (IgY, IgM, and IgA) were found in the vaccinated birds. Metagenomics analysis of the cecal bacterial community in 21-day old birds showed the presence of Firmicutes (90%), Proteobacteria (5%), Actinobacteria (2%), and Bacteroidetes (2%). In the vaccinated group, an effect of BACI was noted on Proteobacteria (P = 0.03). Vaccination and/or dietary treatments influenced the population of Lactobacillaceae, Enterobacteriaceae, Clostridiaceae, and Streptococcaceae which were among the most abundant families. Overall, this study revealed that besides their beneficial effects on performance, alike bacitracin, berry pomaces in poultry feed have profound impacts on the chicken cecal microbiota and blood metabolites that could be influenced by vaccination against coccidiosis.

Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer's disease.

Alzheimer's disease (AD) affects cognitive modalities that are known to be regulated by adult neurogenesis, such as hippocampal- and olfactory-dependent learning and memory. However, the relationship between AD-associated pathologies and alterations in adult neurogenesis has remained contentious. In the present study, we performed a detailed investigation of adult neurogenesis in the triple transgenic (3xTg) mouse model of AD, a unique model that generates both amyloid plaques and neurofibrillary tangles, the hallmark pathologies of AD. In both neurogenic niches of the brain, the hippocampal dentate gyrus and forebrain subventricular zone, we found that 3xTg mice had decreased numbers of (i) proliferating cells, (ii) early lineage neural progenitors, and (iii) neuroblasts at middle age (11months old) and old age (18months old). These decreases correlated with major reductions in the addition of new neurons to the respective target areas, the dentate granule cell layer and olfactory bulb. Within the subventricular zone niche, cytological alterations were observed that included a selective loss of subependymal cells and the development of large lipid droplets within the ependyma of 3xTg mice, indicative of metabolic changes. Temporally, there was a marked acceleration of age-related decreases in 3xTg mice, which affected multiple stages of neurogenesis and was clearly apparent prior to the development of amyloid plaques or neurofibrillary tangles. Our findings indicate that AD-associated mutations suppress neurogenesis early during disease development. This suggests that deficits in adult neurogenesis may mediate premature cognitive decline in AD.

Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease.

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, r2 = -0.367; protein, r2 = -0.326) and the accumulation of paired helical filament tau (mRNA, r2 = -0.230; protein, r2 = -0.119), but weakly with insoluble amyloid-beta 42 (mRNA, r2= -0.090; protein, r2 = -0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r2= +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-beta and tau in the cerebral cortex of persons with AD.