Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2.

BACKGROUND: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer's disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release. METHODOLOGY/FINDINGS: We first showed that application of 50 nM Aβ42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, Aβ42 can be detected at the presynaptic terminals where it interacts with Synaptophysin. Furthermore, data from dissociated hippocampal neurons as well as biochemical data provide evidence that Aβ42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that Aβ42 affects baseline transmission. CONCLUSIONS/SIGNIFICANCE: Our observations provide a necessary and timely insight into cellular mechanisms that underlie the initial pathological events that lead to synaptic dysfunction in Alzheimer's disease. Our results demonstrate a new mechanism by which Aβ42 affects synaptic activity

What is the nature of peer interactions in children with language disorders? A qualitative study of parent and practitioner views

Background and aims: Children with Language Disorders (LDs) can exhibit increased levels of social withdrawal, aggression and problems managing social conflicts. The reasons underlying this pattern of social interaction profiles remain unclear. This qualitative study aimed to document the nature of social interactions between children with LDs and their peers, and to evaluate explanations for their social behaviour, as understood by parents and practitioners. Methods: This study focused on children with LDs who spend school hours with other children with LDs. Three parent focus groups (n ¼ 8) and three practitioner focus groups (n ¼ 10) were conducted with parents of children aged 4–12 attending specialist language schools and practitioners working at these schools. This was a mixed clinical sample. All children of participating parents had LD as their primary area of need, which was the reason they required specialist schooling. Focus groups were conducted across two specialist schools in the UK between March and June 2018. Results: An inductive reflective thematic analysis of the data identified three themes; social knowledge, coping strategies, and emotional competence. Parents and school staff reported that children with LDs experience difficulties managing peer interactions due to a combination of challenges including difficulties with understanding and regulating emotions, and difficulties understanding social situations. Some of the children with LDs were described as having developed strategies to cope with their challenges, for example imposing structure on their social interactions to manage uncertainty, which has implications for their social interactions with peers. Conclusions: Children with LDs have difficulties understanding emotions, difficulties understanding their peer’s intentions and difficulties resolving conflict situations independently according to their parents and practitioners working with these children. Participants proposed a novel explanation that social withdrawal may be used adaptively by children with LDs to process information. This study demonstrates the complexity of the relationship between Language Disorders and peer interaction profiles. Implications: Suggestions are offered regarding future research directions, such as investigating the specific contribution language skills make to children’s emotion understanding, to better understand the reasons for peer interaction difficulties in children with Language Disorders

Combined tissue and fluid proteomics with Tandem Mass Tags to identify low-abundance protein biomarkers of disease in peripheral body fluid: An Alzheimer's Disease case study

RATIONALE: Ideal biomarkers are present in readily accessible samples including plasma and cerebrospinal fluid (CSF), and are directly derived from diseased tissue, therefore likely to be of relatively low abundance. Traditional unbiased proteomic approaches for biomarker discovery have struggled to detect low-abundance markers due to the high dynamic range of proteins, the predominance of hyper-abundant proteins, and the use of data-dependent acquisition mass spectrometry (MS). To overcome these limitations and improve biomarker discovery in peripheral fluids, we have developed TMTcalibrator™; a novel MS workflow combining isobarically labelled diseased tissue digests in parallel with an appropriate set of labelled body fluids to increase the chance of identifying low-abundance, tissue-derived biomarkers. METHODS: A disease relevant cell line was labelled with TMT® in a range of concentrations generating a multi-point calibration curve. Peripheral biofluid samples were labelled with the remaining tags and quantitative analysis was performed using an Orbitrap Fusion Tribrid mass spectrometer with a Top10 CID-HCD MS3 synchronous precursor selection (SPS) method. SPS allowed direct analysis of non-depleted, unfractionated CSF samples with complete profiling of six individual samples requiring only 15 hours of MS time, equivalent to 1.5 h per sample. RESULTS: Using the TMTcalibrator™ workflow allowed the identification of several markers of microglia activation that are differentially quantified in the CSF of patients with Alzheimer's disease (AD). We report peptides from 41 proteins that have not previously been detected in the CSF, that appear to be regulated by at least 60% in AD. CONCLUSIONS: This study has demonstrated the benefits of the new TMTcalibrator™ workflow and the results suggest this is a suitable and efficient method of detecting low-abundance peptides within biological fluids. The use of TMTcalibrator™ in further biomarker discovery studies should be considered to overcome some of the limitations commonly associated with more conventional approaches

Ecological implications of fine-scale fire patchiness and severity in tropical savannas of northern Australia

Research ArticleUnderstanding fine-scale fire patchiness has significant implications for ecological processes and biodiversity conservation. It can affect local extinction of and recolonisation by relatively immobile fauna and poorly seed-dispersed flora in fire-affected areas. This study assesses fine-scale fire patchiness and severity, and associated implications for biodiversity, in north Australian tropical savanna systems. We used line transects to sample burning patterns of ground layer vegetation in different seasons and vegetation structure types, within the perimeter of 35 fires that occurred between 2009 and 2011. We evaluated two main fire characteristics: patchiness (patch density and mean patch length) and severity (inferred from char and scorch heights, and char and ash proportions). The mean burned area of ground vegetation was 83 % in the early dry season (EDS: May to July) and 93 % in the late dry season (LDS: August to November). LDS fires were less patchy (smaller and fewer unburned patches), and had higher fire severity (higher mean char and scorch heights, and twice the proportion of ash) than EDS fires. Fire patchiness varied among vegetation types, declining under more open canopy structure. The relationship between burned area and fire severity depended on season, being strongly correlated in the EDS and uncorrelated in the LDS. Simulations performed to understand the implications of patchiness on the population dynamics of fire-interval sensitive plant species showed that small amounts of patchiness substantially enhance survival. Our results indicate that the ecological impacts of high frequency fires on firesensitive regional biodiversity elements are likely to be lower than has been predicted from remotely sensed studies that are based on assumptions of homogeneous burninginfo:eu-repo/semantics/publishedVersio

Synergistic effects of high fat feeding and apolipoprotein E deletion on enterocytic amyloid-beta abundance

Background: Amyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo) E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT) and apo E knockout (KO) mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w) unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls. Results: The saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice. Conclusion: The findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity

Don't lose sight of the importance of the individual in effective falls prevention interventions

Falls remain a major public health problem, despite strong growth in the research evidence of effective single and multifactorial interventions, particularly in the community setting. A number of aspects of falls prevention require individual tailoring, despite limitations being reported regarding some of these, including questions being raised regarding the role of falls risk screening and falls risk assessment. Being able to personalise an individual's specific risk and risk factors, increase their understanding of what interventions are likely to be effective, and exploring options of choice and preference, can all impact upon whether or not an individual undertakes and sustains participation in one or more recommendations, which will ultimately influence outcomes. On all of these fronts, the individual patient receiving appropriate and targeted interventions that are meaningful, feasible and that they are motivated to implement, remains central to effective translation of falls prevention research evidence into practice