Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of ...synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
Depression not only perturbs the gut microbiota at abundance level but that it also alters the fecal metabolic phenotype. In addition, there was a strong correlation between gut microbiota and fecal ...metabolites.
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•A combined 16S rRNA gene sequencing and MS-based metabolomics has been established.•Depression led to significant changes of gut microbiota at phylum and genus levels.•Depression led to significant changes of fecal metabolic phenotype.•Strong correlation of gut microbiota, fecal metabolites, and catecholamine levels.
As a prevalent, life-threatening and highly recurrent psychiatric illness, depression is characterized by a wide range of pathological changes; however, its etiology remains incompletely understood. Accumulating evidence supports that gut microbiota affects not only gastrointestinal physiology but also central nervous system (CNS) function and behavior through the microbiota-gut-brain axis. To assess the impact of gut microbiota on fecal metabolic phenotype in depressive conditions, an integrated approach of 16S rRNA gene sequencing combined with ultra high-performance liquid chromatography-mass spectrometry (UHPLC–MS) based metabolomics was performed in chronic variable stress (CVS)-induced depression rat model. Interestingly, depression led to significant gut microbiota changes, at the phylum and genus levels in rats treated with CVS compared to controls. The relative abundances of the bacterial genera Marvinbryantia, Corynebacterium, Psychrobacter, Christensenella, Lactobacillus, Peptostreptococcaceae incertae sedis, Anaerovorax, Clostridiales incertae sedis and Coprococcus were significantly decreased, whereas Candidatus Arthromitus and Oscillibacter were markedly increased in model rats compared with normal controls. Meanwhile, distinct changes in fecal metabolic phenotype of depressive rats were also found, including lower levels of amino acids, and fatty acids, and higher amounts of bile acids, hypoxanthine and stercobilins. Moreover, there were substantial associations of perturbed gut microbiota genera with the altered fecal metabolites, especially compounds involved in the metabolism of tryptophan and bile acids. These results showed that the gut microbiota was altered in association with fecal metabolism in depressive conditions. These findings suggest that the 16S rRNA gene sequencing and LC–MS based metabolomics approach can be further applied to assess pathogenesis of depression.
Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase ...(BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.
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•Lowering the BDK:PPM1K ratio improves glucose and lipid homeostasis in obese rats•ATP-citrate lyase (ACL) is an alternate BDK/PPM1K substrate•Overexpression of BDK in liver increases ACL phosphorylation and de novo lipogenesis•The ChREBP-β transcription factor increases BDK and decreases PPM1K expression
Branched-chain amino acids (BCAA) are strongly associated with metabolic diseases. White et al. demonstrate that the kinase (BDK) and phosphatase (PPM1K) that regulate a rate-limiting BCAA metabolic enzyme, BCKDH, also regulate ATP-citrate lyase, a key lipogenic enzyme, thus identifying a new regulatory node that integrates BCAA and lipid metabolism.
Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are ...incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin’s function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders.
•Oxytocin in the olfactory system is required for social recognition•Oxytocin activates cortical top-down inputs to olfactory bulb interneurons•Top-down inputs generate states of high signal-to-noise in odor coding
Oettl et al. found that oxytocin transforms sensory channels for optimized processing of cues through cortical top-down recruitment of interneurons. These novel oxytocin actions are required for social recognition and may be of relevance to sensory perception deficits in autism.
Internal hemorrhaging is a leading cause of death after traumatic injury on the battlefield. Although several surgical approaches such as the use of fibrin glue and tissue adhesive have been ...commercialized to achieve hemostasis, these approaches are difficult to employ on the battlefield and cannot be used for incompressible wounds. Here, we present shear-thinning nanocomposite hydrogels composed of synthetic silicate nanoplatelets and gelatin as injectable hemostatic agents. These materials are demonstrated to decrease in vitro blood clotting times by 77%, and to form stable clot-gel systems. In vivo tests indicated that the nanocomposites are biocompatible and capable of promoting hemostasis in an otherwise lethal liver laceration. The combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency conditions.
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to ...selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.
Synopsis
This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease.
An antibody directed to the stalk region of TREM2 prevents its shedding and increases cell autonomous signaling.
Addition of this TREM2 antibody to myeloid cells in vitro stimulates phagocytosis, and improves cell survival.
TREM2 antibody treatment increases TREM2 expression on brain microglia, decreases homeostatic markers and reduces amyloid plaque pathology in a mouse model of Alzheimer's disease.
Antibody mediated stimulation of TREM2 signaling may be efficacious in Alzheimer's disease as well as other neurodegenerative disorders and obesity‐associated metabolic syndromes.
This study describes the discovery and characterization of a novel TREM2 antibody, which induces protective microglial functions and provides a basis for the development of human antibodies with a similar mechanistic profile for treatment of Alzheimer's disease.
There is a growing need for a better understanding of sex differences in animal models of psychiatric disorders. The elevated plus-maze (EPM) test and large open field (LOF) test are widely used to ...study anxiety-like behavior in rodents. Our studies explored sex differences in anxiety and activity parameters in the LOF and EPM and determined whether these parameters correlate within and between tests. Drug naïve adult male and female Wistar rats (n = 47/sex) were used for the studies, and the rats were tested for 5 min in the EPM and 10 min in the LOF. The females spent more time on the open arms of the EPM and made more open arms entries than the males. The females also spent more time in the center zone of the LOF and made more center zone entries. The females traveled a greater distance in the LOF and EPM. There was a moderate positive correlation between time on the open arms of the EPM and time in the center zone of the LOF. There was also a moderate positive correlation between open arms entries in the EPM and center zone entries in the LOF. A hierarchical cluster analysis revealed one cluster with LOF parameters, one cluster with EPM parameters, and one cluster with parameters related to the avoidance of open spaces. In conclusion, these findings indicate that female rats display less anxiety-like behavior in the EPM and LOF. Furthermore, there are sex differences for almost all behavioral parameters in these anxiety tests.
•Females are less anxious than males in the open field and elevated plus-maze test.•Females are more active than males in the open field and elevated plus-maze test.•There is a strong correlation between behavioral parameters in anxiety tests.•Behavioral parameters within tests are more similar than parameters between tests.
Ag/Ag@AgCl/ZnO hybrid nanostructures are embedded in a hydrogel by a simple two-step technique. The Ag/Ag@AgCl nanostructures are assembled in the hydrogel via ultraviolet light chemical reduction ...followed by incorporation of ZnO nanostructures by NaOH precipitation. The hydrogel accelerates wound healing and exhibits high antibacterial efficiency against both Escherichia coli and Staphylococcus aureus under visible light irradiation. The Ag/Ag@AgCl nanostructures enhance the photocatalytic and antibacterial activity of ZnO due to the enhancement of reactive oxygen species by visible light. This hydrogel system kills 95.95% of E. coli and 98.49% of S. aureus within 20 min upon exposure to simulated visible light, and rapid sterilization plays a crucial role in wound healing. In addition, this system provides controllable, sustained release of silver and zinc ions over a period of 21 days arising from the reversible swelling–shrinking transition of the hydrogel triggered by the changing pH value in the biological environment. About 90% Zn2+ release is observed in the acidic environment after 3 days, whereas only 10% Zn2+ release occurs in the neutral environment after 21 days. In vivo results show that release of Ag+ and Zn2+ stimulates the immune function to produce a large number of white blood cells and neutrophils (2–4 times more than the control), thereby producing the synergistic antibacterial effects and accelerated wound healing.
During the lactation period, rat pups are fed by the dam, and the patterns of mother-pup interaction change during this period. Additionally, there are changes in feeding; first, mother´s milk is the ...only food needed for sustenance, and later, it is combined with solid food and water. GH serum concentrations depend on both maternal-pup interaction and energy metabolism. In the artificial rearing (AR) procedure, pups are deprived of mother-pup interaction, and the feeding pattern is controlled. This rearing paradigm has been used in rats to analyze the effects of maternal deprivation on social behavior. In the present study, we analyzed the variation in GH, acylated ghrelin and IGF-1 serum concentrations throughout the lactation period in AR pups. At pnd7, the maternal rearing (MR) pups responded to a 4 h fast with a drop in GH serum concentration, which is a well-known response to maternal deprivation. GH serum levels in the AR pups did not change, suggesting an adaptation phenomenon. A dopamine inhibitory effect of GH secretion was observed in pnd7 cultured somatotropes, suggesting dopamine regulation of GH secretion at this age. Acylated ghrelin serum levels in the AR pups showed an inverted pattern compared to that in the MR pups, which was related to the artificial feeding pattern. IGF-1 serum levels were lower in the AR pups than in MR pups, which was associated with hepatic GH resistance and with low Igf1 mRNA expression at pnd7. Interestingly, at pnd14, both pup groups showed high hepatic Igf1 mRNA expression but low IGF-1 serum levels, and this was inverted at pnd21. However, serum glucose levels were lower in the AR pups at pnd14 but reached the same levels as the MR pups at pnd21. Moreover, hepatomegaly and higher hepatic GH-receptor levels were observed in the AR pups at pnd21, which was in agreement with an absence of a solid food meal. During AR, the pups lost the maternal interaction-stimulated GH secretion, which correlated with lower IGF-1 serum levels during the first week of postnatal development. Later, the AR pups exhibited hepatic responses, in order to satisfy the metabolic demand for the normal weaning, with low carbohydrates levels in their meal.
Early postnatal overfeeding (PO) induces long-term overweight and reduces brown adipose tissue (BAT) thermogenesis. Exercise has been suggested as a possible intervention to increase BAT function. In ...this study, we investigated chronical effects of moderate-intensity exercise in BAT function in postnatal overfed male Wistar rats METHODS: Litters' delivery was on postnatal-day 0 - PN0. At PN2, litters were adjusted to nine (normal litter - NL) or three pups (small litter - SL) per dam. Animals were weaned on PN21 and in PN30 randomly divided into sedentary (NL-Sed and SL-Sed) or exercised (NL-Exe and SL-Exe), N of 14 litters per group. Exercise protocol started (PN30) with an effort test; training sessions were performed three times weekly at 60% of the VO
achieved in effort test, until PN80. On PN81, a temperature transponder was implanted beneath the interscapular BAT, whose temperature was assessed in periods of lights-on and -off from PN87 to PN90. Sympathetic nerve activation of BAT was registered at PN90. Animals were euthanized at PN91 and tissues collected RESULTS: PO impaired BAT thermogenesis in lights-on (p
< 0.0001) and -off (p
< 0.01). Exercise increased BAT temperature in lights-on (p
< 0.0001). In NL-Exe, increased BAT activity was associated with higher sympathetic activity (p
< 0.05), β3-AR (p
< 0.001), and UCP1 (p
< 0.001) content. In SL-Exe, increasing BAT thermogenesis is driven by a combination of tissue morphology remodeling (p
< 0.0001) with greater effect in increasing UCP1 (p
< 0.001) and increased β3-AR (p
< 0.001) content.
Moderate exercise chronically increased BAT thermogenesis in both, NL and SL groups. In NL-Exe by increasing Sympathetic activity, and in SL-Exe by a combination of increased β3-AR and UCP1 content with morphologic remodeling of BAT. Chronically increasing BAT thermogenesis in obese subjects may lead to higher overall energy expenditure, favoring the reduction of obesity and related comorbidities.
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