Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding

<p>Abstract</p> <p>Background</p> <p>Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the <it>trans</it>-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1.</p> <p>Results</p> <p>Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner <it>et al </it>(2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPα.</p> <p>Conclusion</p> <p>Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.</p

The Notch intracellular domain represses CRE-dependent transcription

AbstractMembers of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression

Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice

As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of Abeta pathology. An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta underlies the reduction in plaques. Increased tau phosphorylation correlated with reduced tau-phosphatase PP2A, despite an inhibition of the tau-kinase glycogen synthase kinase-3. Our findings demonstrate that disruption of IIS in Tg2576 mice has divergent effects on pathological processes-a reduction in aggregated Abeta but an increase in tau phosphorylation. However, as these effects are accompanied by improvement in behavioural deficits, our findings suggest a novel protective effect of disrupting IRS2 signalling in AD which may be a useful therapeutic strategy for this condition

Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods—quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis

The impact of digitalisation on students’ language learning in grades 4-6 : An empirical study of the teachers’ view of the use of digital tools in English teaching

Dagens globaliserade samhälle är sammankopplat bl.a. via den digitala tekniken, vilket bidrar till utvecklingen av individens språk och kommunikationsförmåga. Dagens barn utvecklar sitt engelska språk och digitala kompetenser i skolan men även utanför genom interaktion via sociala medier och spelifiering. Detta faktum stärks såväl av tidigare forskning som presenteras i denna studie, som av de intervjuade lärarna som också presenteras här. Den sociokulturella teorin och multiliteracitet-teorin (multiliteracies) anses vara relevanta i denna studie eftersom båda anses bidra till elevers utveckling av språket, kommunikationsförmågan samt digitala kompetenser.   Syftet med denna studie är att undersöka hur engelsklärare som undervisar i årskurs 4–6 ser på implementering av digitala verktyg i engelskundervisningen, vilka fördelar och nackdelar kan det finnas enligt lärare samt vilka konkreta digitala verktyg som används. Denna studie vilar på den kvalitativa ansatsen. Den är viktig eftersom fokuset ligger på individens personliga tankar, idéer samt resonemang kopplad till språkinlärning och digitala verktyg. För att få svar på studiens frågeställningar användes semistrukturerade intervjuer.   Resultatet visar att engelsklärarna är positivt inställda till digitaliseringen och de använder olika digitala verktyg i sin engelskundervisning men även i andra ämnen dagligen. Dock visar studien att lärarna efterfrågar fortbildningar inom engelskan kopplade till digitala verktyg, bl.a. hur vissa andra program, hemsidor samt appar som lärarna inte har använt kan implementeras i engelskan för att stärka elevernas språkinlärning. De digitala verktygen som används är oftast filmer, musik, kunskapsspel, där Youtube, SLI, British Council Kids/Teens, Elevspel, Bingel och Kahoot används som mest. Dock anser de flesta engelsklärarna i studien att papper och penna inte bör bytas ut mot digitala verktyg, utan digitala verktyg är och bör vara ett komplement i språkundervisningen.

The impact of the classroom environment and working methods on students' oral ability : An empirical study from a teacher's perspective

Kommunikation kan ske via tal, skrift eller kroppsspråk. Elever kommunicerar dagligen både hemma och i skolan. Syftet med studien är att undersöka vad som kan påverka elevers muntliga förmåga, där studien är avgränsad till kommunikativa förhållningssätt, arbetsmetoder och klassrumsmiljö. En annan avgränsning är att studien genomförs på endast en skola eftersom det är begränsat med tid och resurser. Studien grundas på en kvalitativ ansats och de verktyg som används är observationer i två klasser och intervjuer med två lärare. Det hermeneutiska paradigmet och det sociokulturella perspektivet är den teoretiska ramen för studien. Under observationerna framkommer det att dialogisk, interaktiv, icke- interaktiv och auktoritativ kommunikation genomsyrar klassrummen. Dessutom visar resultatet att den arbetsmetod som lärarna använder mest är grupparbeten och att mindre grupper är mest givande. Det som framkommer under intervjuerna är att lärarna anser att relationer och motivation är sammanvävda och påverkar varandra, vilket överensstämmer med den tidigare forskningen.

Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer’s Disease Diagnosis

Background:Alzheimer’s disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer’s disease. Objective:To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer’s disease. Methods:SOMAscan assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer’s disease. Results:Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer’s disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer’s-type diagnosis are factors IX and XI—an increase in both factors is associated with a reduction in cognitive function. Conclusion:Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer’s-type neurodegeneration

SOMAscan-based proteomic measurements of plasma brain natriuretic peptide are decreased in mild cognitive impairment and in Alzheimer's dementia patients

Alzheimer's disease represents the most common age-related neurodegenerative disorder and a leading cause of progressive cognitive impairment. Predicting cognitive decline is challenging but would be invaluable in an increasingly aging population which also experiences a rising cardiovascular risk. In order to examine whether plasma measurements of one of the established biomarkers of heart failure, brain natriuretic peptide (BNP), reflect a decline in cognitive function, associated with Alzheimer's disease neurodegeneration, BNP levels were analysed, by using a novel assay called a SOMAscan, in 1. cognitively healthy, control subjects; 2. subjects with mild cognitive impairment, and 3. subjects with Alzheimer's disease. The results of our study show that the levels of the BNP were significantly different between the three types of diagnoses (p < 0.05), whereby subjects with mild cognitive impairment had the lowest mean BNP value, and healthy subjects had the highest BNP value. Importantly, our results show that the levels of the BNP are influenced by the presence of at least one APOE4 allele in the healthy (p < 0.05) and in the Alzheimer's disease groups of subjects (p < 0.1). As the levels of the BNP appear to be independent of the APOE4 genotype in subjects with mild cognitive impairment, the results of our study support inclusion of measurements of plasma levels of the BNP in the list of the core Alzheimer's disease biomarkers for identification of the mild cognitive impairment group of patients. In addition, the results of our study warrant further investigations into molecular links between Alzheimer's disease-type cognitive decline and cardiovascular disorders