Alzheimer's disease pathology:pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD

Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.</p

Biologische bestrijding van weekhuidmijten in bromelia

Tarsonemidae (weekhuidmijten) zijn belangrijke plaagorganismen in de teelt van bromelia-achtigen. In Nederland werden ze voor het eerst aangetroffen in 1989 op Neoregelia carolinae en geïdentificeerd door de PD als Steneotarsonemus ananas, de ananasmijt. Weekhuidmijten zijn zeer kleine plantzuigende mijtjes van slechts 0,2 mm groot. Ze kunnen verschillende soorten schade aan de Bromelia’s veroorzaken: necrotische plekken aan de bladeren en jonge plantdelen, bruin-rode bladstrepen en misvorming van de bloeiwijze. De chemische bestrijding is lastig, mede door het verdwijnen van langwerkende acariciden. Het onderzoek waar in dit rapport verslag wordt gemaakt is uitgevoerd tussen 2008 en 2010. Het is opgestart mede naar aanleiding van oriënterende proeven (Messelink en Van Holstein-Saj, 2007) met potentiële biologische bestrijders van deze plaag. Doel van dit vervolg-onderzoek was om basiskennis over de biologie van ananasmijten op Bromelia uit te breiden, wat van belang is voor het ontwikkelen van een goede bestrijdingsstrategie. Gedurende het onderzoek zijn monsters afkomstig van praktijkbedrijven (meestal vermeerderingsbedrijven, maar ook productiebedrijven) onderzocht. Op bromelia’s met “ananasmijtsymptomen” werden verschillende soorten weekhuidmijten (familieTarsonemidae) gevonden. Het betrof zowel planten-eters (Steneotarsonemus-soorten) als onschadelijke schimmel-eters (Tarsonemus-soorten). Binnen het geslacht Steneotarsonemus konden twee soorten worden onderscheiden. Beide zijn waarschijnlijk species novae (niet eerder beschreven soorten). De echte ananasmijt, Steneotarsonemus ananas, werd niet aangetroffen. Weekhuidmijten veroorzaken verkleuringen en misvormingen, die vaak pas geruime tijd na de aantasting zichtbaar worden. De mijten zelf kunnen inmiddels al weer vertrokken zijn naar geschiktere delen van de waardplant (groeipunten). Het onderzoek naar besmettingsbronnen en verspreidingswijze van de weekhuidmijten heeft zich vooral gericht op vermeerderingsbedrijven. Oudere bromelia’s lijken minder gevoelig voor aantasting, maar blijven wel een mogelijke besmettingsbron Steneotarsonemus is in hoge mate gebonden aan levend plantmateriaal. Grond en fust zijn geen waarschijnlijke besmettingsbronnen. De voortplantingssnelheid is in principe zeer hoog (extreem korte generatieduur), maar de actieve verspreiding van plant naar plant is traag. Planten moeten elkaar daartoe raken; verspreiding via grond of tafel is niet waarschijnlijk. Passieve verspreiding is mogelijk via mensen, verplaatsen van planten en volgens de literatuur ook via vliegende insekten. Of dit laatste in de praktijk een rol speelt, is niet bekend. Bodemgebonden roofmijten bleken zeer algemeen op de vermeerderingsbedrijven. Naast de gebruikelijke soorten identificeerden we Lasioseius fimetorum en Armascirus taurus. Volgens onze laboratoriumobservaties zijn weekhuidmijten geen geschikte prooi (want te klein?) voor grotere roofmijten zoals Hypoaspis. Wel geschikt zijn sommige kleinere roofmijtsoorten van de familie Phytoseiidae. Lasioseius fimetorum, qua grootte een “middenklasser”, krijgt het voordeel van de twijfel. Van de momenteel commercieel beschikbare roofmijten geldt Amblyseius barkeri als de meest geschikte predator van weekhuidmijten. Op bedrijven waar roofmijten waren uitgezet, werden de telers geïnterviewd over de toegepaste strategie en werden populatiebemonsteringen van de roofmijten uitgevoerd. Wij slaagden er niet in halfwas bromelia’s langdurig met Phytoseiidae (Amblyseius swirskii en Amblyseius barkeri) te koloniseren

Interplay between chromophore binding and domain assembly by the B₁₂-dependent photoreceptor protein, CarH.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-05-01, epub 2021-05-05Publication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Grant(s): BB/L002655/1, BB/L016486/1, BB/M011208/1Organisms across the natural world respond to their environment through the action of photoreceptor proteins. The vitamin B12-dependent photoreceptor, CarH, is a bacterial transcriptional regulator that controls the biosynthesis of carotenoids to protect against photo-oxidative stress. The binding of B12 to CarH monomers in the dark results in the formation of a homo-tetramer that complexes with DNA; B12 photochemistry results in tetramer dissociation, releasing DNA for transcription. Although the details of the response of CarH to light are beginning to emerge, the biophysical mechanism of B12-binding in the dark and how this drives domain assembly is poorly understood. Here - using a combination of molecular dynamics simulations, native ion mobility mass spectrometry and time-resolved spectroscopy - we reveal a complex picture that varies depending on the availability of B12. When B12 is in excess, its binding drives structural changes in CarH monomers that result in the formation of head-to-tail dimers. The structural changes that accompany these steps mean that they are rate-limiting. The dimers then rapidly combine to form tetramers. Strikingly, when B12 is scarcer, as is likely in nature, tetramers with native-like structures can form without a B12 complement to each monomer, with only one apparently required per head-to-tail dimer. We thus show how a bulky chromophore such as B12 shapes protein/protein interactions and in turn function, and how a protein can adapt to a sub-optimal availability of resources. This nuanced picture should help guide the engineering of B12-dependent photoreceptors as light-activated tools for biomedical applications

Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons

Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton

Effects of particle size on CO2 reduction and discharge characteristics in a packed bed plasma reactor

Current understanding of the behaviour of plasma discharges within packed bed reactors (PBRs) is very poor, and the effects of many of the parameters that can be varied are still unknown. This article investigates the effects of particle size (180 μm to 2000 μm) of two different commonly used packing materials (Al2O3 and BaTiO3) on the conversion of CO2 in PBRs. The reactor behaviour is observed through determination of product gas composition and plasma power consumption in order to determine CO2 conversion and reactor efficiency. Electrical characterisation techniques are used to determine reactor burning voltage, and capacitances. These capacitances are subsequently used to quantify the occurrence of reactor partial discharging over a range of different operating conditions. The results indicate that smaller particles (down to 180 μm) can significantly increase CO2 conversion by up to 70%, provided that the voltage applied is sufficiently high to generate a discharge in the void spaces of the packing material. However, with decreasing particle size, the reactor burning voltage is found to increase rapidly, as well as the tendency of the reactor towards partial discharging

Bestrijding van tabakswittevlieg, Bemisia tabaci, met roofmijten in poinsettia

Sinds 1987 wordt op meerdere sierteeltbedrijven en op een groeiend aantal groentebedrijven onder glas tabakswittevlieg, Bemisia tabaci (Gennadius) aangetroffen. De soort zorgt voor onrust in de tuinbouw omdat ze een groot aantal virusziekten kan overbrengen en wordt beschouwd als moeilijker te bestrijden dan kaswittevlieg. In pionsettia veroorzaakt tabakswittevlieg cosmetische schade, en bemoeilijkt zelfs bij lage dichtheden verhandelbaarheid en export. Het doel van dit onderzoek was het bepalen van de effectiviteit van twee soorten roofmijten, Amblyseius swirskii e Euseius ovalis, op poinsettiaplanten bij twee temperatuurregimes. Zowel kaswittevlieg als tabakswittevlieg bleken een geschikte prooi voor beide roofmijten te zij

Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors

The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through β1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain

Cytokine responses to repeated, prolonged walking in lean versus overweight/obese individuals.

OBJECTIVES: Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals. DESIGN: Lean (n=25, BMI 22.9±1.5kg/m2) and age-/sex-matched overweight/obese (n=25; BMI 27.9±2.4kg/m2) individuals performed walking exercise for 30, 40 or 50km per day on four consecutive days (distances similar between groups). METHODS: Circulating cytokines (IL-6, IL-10, TNF-α, IL-1β and IL-8) were examined at baseline and <30min after the finish of each exercise day. RESULTS: At baseline, no differences in circulating cytokines were present between groups. In response to prolonged exercise, all cytokines increased on day 1 (IL-1β: P=0.02; other cytokines: P<0.001). IL-6 remained significantly elevated during the 4 exercise days, when compared to baseline. IL-10, TNF-α, IL-1β and IL-8 returned to baseline values from exercise day 2 (IL-10, IL-1β, IL-8) or exercise day 3 (TNF-α) onward. No significant differences were found between groups for all cytokines, except IL-8 (Time*Group Interaction P=0.02). CONCLUSIONS: These data suggest the presence of early adaptive mechanisms in response to repeated prolonged walking, demonstrated by attenuated exercise-induced elevations in cytokines on consecutive days that occur similar in lean and overweight/obese individuals

Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits

Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mic