Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson’s and Alzheimer’s Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer’s Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED “Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)”. HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978).Peer reviewe

A Glial Role in the Action of Electroconvulsive Therapy

The aim of the current thesis was to investigate glial responses to electroconvulsive seizures (ECS), an animal model of the fast-acting antidepressant treatment electroconvulsive therapy (ECT). Depression, a common and devastating disorder, has in recent years been associated with volumetric changes in prefrontal cortex, hippocampus and amygdala, brain regions known to be implicated in emotional behavior. Post-mortem analysis of brain tissue from depressed patients, have suggested that neuronal and glial pathology, seen both as changes in cellular densities and glial cell loss, may underlie the depression-associated volumetric changes. The observations that depressed patients often display high levels of the stress hormone cortisol, and that elevated levels of cortisol have been linked with both hippocampal volume reductions and depression, have lead to the assumption that cortisol may underlie the volumetric changes seen in depressed patients. Support for this idea is found in preclinical studies showing that corticosterone (the rat homologue to cortisol) induce both depression-like behavior and hippocampal volume reductions. Studies have also shown that high levels of corticosterone suppress the formation of new neurons and glial cells in rat hippocampus. The studies of this thesis demonstrate that the antidepressant treatment modality ECS upregulates glial proliferation and, moreover, opposes the inhibitory effect of corticosterone on glial cell renewal. We also demonstrate that ECS, without inducing reactive gliosis (a hallmark of brain damage), increase glial cell activity. Given that glial cells (by supporting, communicating with and nourishing the surrounding neurons) play a vital role in neuronal network, we hypotehesize that these glial cell responses may, at least in part, be involved in the antidepressant action of ECT

Inquiry practises through NTA -in relation to students learning : Intervention study in grade 3 with the assignment färgerna i färgen

Sammanfattning Syftet med vår studie är att bidra med kunskap om hur eleverna i lågstadiet tillägnar sig begreppskunskaper och förmåga att genomföra systematiska undersökningar när de undervisas genom NTA i ämnet kemi. Studien genomfördes i en årskurs 3 med NTA-uppdraget färgerna i färgen. Vi valde att genomföra en kvalitativ interventionsstudie med strategin designbaserad studie. Vid två lektionstillfällen agerade vi själva lärare och observatör. Lektion A planerades efter NTA’s lärarhandledning. Efter analys av lektion A genomfördes en förändring till lektion B. Förändringarna av lektionen var visuellt stöd och tydligare muntlig stöttning från läraren. Den sociokulturella synen på lärande genomsyrar den aktuella studien och det insamlade resultatet. Resultatet visar att NTA-uppdraget färgerna i färgen bidrar till viss begreppsförståelse för begreppet separera och förmåga att genomföra systematiska undersökningar. Med de förändringar som gjordes till lektion B visade insamlat resultat på en ökad förståelse för begreppet separera och förmåga att genomföra systematiska undersökningar. Därmed dras en möjlig slutsats att verksamma och blivande F-3 lärare kan tillägga visuellt stöd och mer muntlig stöttning i sin undervisning när de använder sig av NTA uppdraget färgerna i färgen.  AbstractThe purpose of our study is to contribute knowledge about how primary school students acquire conceptual knowledge and the ability to conduct systematic investigations when taught through NTA in the subject of chemistry. The study was conducted in a grade 3 through the NTA assignment färgerna i färgen.We chose to conduct a qualitative intervention study with the strategy of design-based study. On two occasions we acted as teachers and observers. In lesson A, the assignment was planned straight from the NTA’s pedagogical plan. After analysis of lesson A we made a change for lesson B. The changes we did to lesson B were adding visual support and more oral support from the teacher. The sociocultural view of learning permeates the current study and the collected results. The results show that the NTA assignment färgerna i färgen contributes to some conceptual understanding of the concept of separation and the ability to conduct systematic investigations. With the changes that were made from the collected results the students showed an increased understanding of the concept of separation and the ability to carry out systematic investigations. Thus, it is concluded that active and prospective F-3 teachers should add visual support and more oral support in their teaching when using NTA assignment färgerna i färgen

Inquiry practises through NTA -in relation to students learning : Intervention study in grade 3 with the assignment färgerna i färgen

Sammanfattning Syftet med vår studie är att bidra med kunskap om hur eleverna i lågstadiet tillägnar sig begreppskunskaper och förmåga att genomföra systematiska undersökningar när de undervisas genom NTA i ämnet kemi. Studien genomfördes i en årskurs 3 med NTA-uppdraget färgerna i färgen. Vi valde att genomföra en kvalitativ interventionsstudie med strategin designbaserad studie. Vid två lektionstillfällen agerade vi själva lärare och observatör. Lektion A planerades efter NTA’s lärarhandledning. Efter analys av lektion A genomfördes en förändring till lektion B. Förändringarna av lektionen var visuellt stöd och tydligare muntlig stöttning från läraren. Den sociokulturella synen på lärande genomsyrar den aktuella studien och det insamlade resultatet. Resultatet visar att NTA-uppdraget färgerna i färgen bidrar till viss begreppsförståelse för begreppet separera och förmåga att genomföra systematiska undersökningar. Med de förändringar som gjordes till lektion B visade insamlat resultat på en ökad förståelse för begreppet separera och förmåga att genomföra systematiska undersökningar. Därmed dras en möjlig slutsats att verksamma och blivande F-3 lärare kan tillägga visuellt stöd och mer muntlig stöttning i sin undervisning när de använder sig av NTA uppdraget färgerna i färgen.  AbstractThe purpose of our study is to contribute knowledge about how primary school students acquire conceptual knowledge and the ability to conduct systematic investigations when taught through NTA in the subject of chemistry. The study was conducted in a grade 3 through the NTA assignment färgerna i färgen.We chose to conduct a qualitative intervention study with the strategy of design-based study. On two occasions we acted as teachers and observers. In lesson A, the assignment was planned straight from the NTA’s pedagogical plan. After analysis of lesson A we made a change for lesson B. The changes we did to lesson B were adding visual support and more oral support from the teacher. The sociocultural view of learning permeates the current study and the collected results. The results show that the NTA assignment färgerna i färgen contributes to some conceptual understanding of the concept of separation and the ability to conduct systematic investigations. With the changes that were made from the collected results the students showed an increased understanding of the concept of separation and the ability to carry out systematic investigations. Thus, it is concluded that active and prospective F-3 teachers should add visual support and more oral support in their teaching when using NTA assignment färgerna i färgen

“Why not cover the metal detector in cardboard and paint it with lots of colours?” : A study of how Bryggan and The Prison and Probation Service support children with incarcerated parents

Uppsatsens syfte var att undersöka hur den ideella föreningen Bryggan och Kriminalvården ger stöd till barn med frihetsberövade föräldrar. Vi ville undersöka hur de yrkesverksamma tar barnets bästa i beaktning och hur de använder och definierar begreppet “barnperspektiv” i sin verksamhet. Studien genomfördes med en kvalitativ metod genom fem intervjuer med yrkesverksamma inom Bryggan och Kriminalvården. Analysen av materialet gjordes med empowerment som teoretisk utgångspunkt. Resultatet visar att Bryggan och Kriminalvården definierar barnperspektiv på olika sätt, men att de båda verksamheterna har en ambition att ha ett bra bemötande i möte med barnen. Som ideell organisation jobbar Bryggan mer direkt med barnen och kan då i större grad tillgodose deras behov jämfört med Kriminalvården som begränsas av lagar och regler. The purpose of this study was to explore how the non-profit organization Bryggan and The Prison and Probation Service support children with incarcerated parents. We wanted to research how the professionals in these organizations have the best interest of the child at hand, and how they use and define “children’s perspective” in their daily work. The qualitative study involved interviewing professionals that worked in the chosen organizations. The analysis was made with empowerment as the theoretical frame of reference. The result of the study shows that Bryggan and the prison service define “children’s perspective” differently. However both organizations aim to meet the children with a good treatment. As a non-profit organization, Bryggan works more towards the children, and can therefore satisfy their needs in a greater extent than the prison service, which are more bound by laws and rules

“Why not cover the metal detector in cardboard and paint it with lots of colours?” : A study of how Bryggan and The Prison and Probation Service support children with incarcerated parents

Uppsatsens syfte var att undersöka hur den ideella föreningen Bryggan och Kriminalvården ger stöd till barn med frihetsberövade föräldrar. Vi ville undersöka hur de yrkesverksamma tar barnets bästa i beaktning och hur de använder och definierar begreppet “barnperspektiv” i sin verksamhet. Studien genomfördes med en kvalitativ metod genom fem intervjuer med yrkesverksamma inom Bryggan och Kriminalvården. Analysen av materialet gjordes med empowerment som teoretisk utgångspunkt. Resultatet visar att Bryggan och Kriminalvården definierar barnperspektiv på olika sätt, men att de båda verksamheterna har en ambition att ha ett bra bemötande i möte med barnen. Som ideell organisation jobbar Bryggan mer direkt med barnen och kan då i större grad tillgodose deras behov jämfört med Kriminalvården som begränsas av lagar och regler. The purpose of this study was to explore how the non-profit organization Bryggan and The Prison and Probation Service support children with incarcerated parents. We wanted to research how the professionals in these organizations have the best interest of the child at hand, and how they use and define “children’s perspective” in their daily work. The qualitative study involved interviewing professionals that worked in the chosen organizations. The analysis was made with empowerment as the theoretical frame of reference. The result of the study shows that Bryggan and the prison service define “children’s perspective” differently. However both organizations aim to meet the children with a good treatment. As a non-profit organization, Bryggan works more towards the children, and can therefore satisfy their needs in a greater extent than the prison service, which are more bound by laws and rules

Amylin alters human brain pericyte viability and NG2 expression

Amylin, a pancreatic β-cell-derived peptide hormone, forms inclusions in brain microvessels of patients with dementia who have been diagnosed with type 2 diabetes and Alzheimer's disease. The cellular localization of these inclusions and the consequences thereof are not yet known. Using immunohistochemical staining of hippocampus and parahippocampal cortex from patients with Alzheimer's disease and non-demented controls, we show that amylin cell inclusions are found in pericytes. The number of amylin cell inclusions did not differ between patients with Alzheimer's disease and controls, but amylin-containing pericytes displayed nuclear changes associated with cell death and reduced expression of the pericyte marker neuron-glial antigen 2. The impact of amylin on pericyte viability was further demonstrated in in vitro studies, which showed that pericyte death increased in presence of fibril- and oligomer amylin. Furthermore, oligomer amylin increased caspase 3/7 activity, reduced lysate neuron-glial antigen 2 levels and impaired autophagy. Our findings contribute to increased understanding of how aggregated amylin affects brain vasculature and highlight amylin as a potential factor involved in microvascular pathology in dementia progression

Levels of retinal IAPP are altered in Alzheimer's disease patients and correlate with vascular changes and hippocampal IAPP levels

Islet amyloid polypeptide (IAPP) forms toxic aggregates in the brain of patients with Alzheimer's disease (AD). Whether IAPP also affects the retina in these patients is still unknown. Levels of IAPP in soluble and insoluble homogenate fractions of retina and hippocampus from AD patients and nondemented controls were analyzed using ELISA. Number of pericytes and vessel length were determined by analysis of immunostained retina and hippocampus. Insoluble retinal fractions of AD patients contained lower levels of unmodified IAPP, whereas soluble retinal fractions contained increased levels of the same. Total IAPP levels and pericyte numbers in retina mirrored corresponding variables in the hippocampus. Moreover, levels of total unmodified IAPP correlated negatively with the vessel length both in retina and hippocampus across the group and positively with pericyte numbers in retina in AD patients. Our studies indicate that changes in brain IAPP are reflected by corresponding levels in the retina. Our results also suggest modification of IAPP as an important event implicated in vascular changes associated with AD