The Formyl Peptide Receptor 2 Regulates Microglial Phenotype Through Immunometabolism: Implications for Alzheimer’s Disease

Microglia are key players in the pathology of Alzheimer’s disease (AD), driving chronic inflammation, oxidative stress, and the altered metabolism seen in the brains of patients. With clinical trials continuing to fail, new approaches towards drug development are critical. Strategies to reduce microglial activation may therefore be a viable therapeutic approach to tackling AD. Formyl peptide receptor 2 (Fpr2), which drives peripheral inflammatory resolution, is expressed in microglia. However, its functional role in neuroinflammation is unclear. This thesis provides evidence to support the peripheral findings of Fpr2 stimulation, wherein it may also hold promise for exploitation as a therapeutic for neurodegenerative disorders, including AD. We also highlight novel findings surrounding the modulation of both oxidative stress and microglial metabolism associated with Fpr2 activation. Under inflammatory conditions, we report that selective agonists for Fpr2 modulate the microglial inflammatory response, actively shifting from a pro-inflammatory to a pro-resolving phenotype, emphasised by the reduction of pro-inflammatory cytokines and concomitant increases in both pro-resolving cytokines and phagocytosis. Metabolic shifting away from glycolysis was also observed for pro-resolving microglia. Moreover, we describe for the first time that Fpr2 completely reverses reactive oxygen species (ROS) production from the mitochondria and NADPH oxidase enzymes following an inflammatory stimulus. We also highlight that the toxic oligomeric amyloid (oAβ) facilitates microglial ROS production and subsequent metabolic changes without triggering an inflammatory response. oAβ facilitated NADPH oxidase activation, which in turn resulted in the activation of glucose 6-phosphate dehydrogenase (G6PD), the rate limiting step for the pentose phosphate pathway. This metabolic pathway is responsible for producing NADPH, which in turn NADPH oxidases exploit for further ROS production. These changes resulted in noticeable reductions in both microglial glycolysis and oxidative phosphorylation. We present data underlining that Fpr2/3 stimulation reverses oAβ-induced ROS production, with a resultant reduction in G6PD activity and the return of homeostatic glycolysis. These oAβ-induced microglial changes triggered the apoptosis of SH-SY5Y cells in co-culture with BV-2 microglia. However, supporting our interest in Fpr2/3 for therapeutic approaches to neurodegenerative diseases, post-treatment with a select agonist for the receptor successfully prevented apoptosis of these neuronal like SH-SY5Y cells. This original data unveils novel functions of Fpr2/3 in the central nervous system (CNS), supplementing the well-established pro-resolving functions the receptor facilitates within the periphery. The combination of pro-resolving, anti-oxidative, immunometabolic and anti-apoptotic functions of Fpr2/3 support the exploitation of this receptor for therapeutic research into multiple different CNS disorders, including AD

Manual Setting

Eyes tired from new media, projections, backlit technologies and digitised images? Enter the world of raw, fresh, immediate sketchbooks, held in the hand, turned with the fingers. In Manual Setting visitors leaf through sketchbooks together with exhibitors: artists, scientists and writers. This enacts the viewing of a notebook as a hand-held, shared and performative activity. Who is revealed during this process of showing and being shown? An enquiry is made concerning intimacy; and the border between personal and private; as well as the provisionally sketched and the finished. Books can often only be exhibited in cases, boxes or frames one page at a time. Handling the sketchbook/notebook repairs the loss of human contact with these objects. There can be a reconciliation with the manual practice of showing to others, activating lively discussion between maker and audience. In the house/gallery setting, several people who keep notebooks, (or what they consider to be sketchbook material), will be situated around the building. These include Dino Alfier, Eleanor Bowen and Paul Ryan (who co-curated this project with Danielle Arnaud), as well as a changing list of invited guests. Saturday 5th February is �Archaeology Day� with guest exhibitors Simon Callery and Dr Helen Wickstead. See website for guests and themes on other days

Archaeology on your farm: gaining from history

Information for land managers and farming advisers within Cranborne Chase and West Wiltshire Downs Area of Outstanding Natural Beauty

Trypanosome outer kinetochore proteins suggest conservation of chromosome segregation machinery across eukaryotes

Kinetochores are multiprotein complexes that couple eukaryotic chromosomes to the mitotic spindle to ensure proper segregation. The model for kinetochore assembly is conserved between humans and yeast, and homologues of several components are widely distributed in eukaryotes, but key components are absent in some lineages. The recent discovery in a lineage of protozoa called kinetoplastids of unconventional kinetochores with no apparent homology to model organisms suggests that more than one system for eukaryotic chromosome segregation may exist. In this study, we report a new family of proteins distantly related to outer kinetochore proteins Ndc80 and Nuf2. The family member in kinetoplastids, KKT-interacting protein 1 (KKIP1), associates with the kinetochore, and its depletion causes severe defects in karyokinesis, loss of individual chromosomes, and gross defects in spindle assembly or stability. Immunopurification of KKIP1 from stabilized kinetochores identifies six further components, which form part of a trypanosome outer kinetochore complex. These findings suggest that kinetochores in organisms such as kinetoplastids are built from a divergent, but not ancestrally distinct, set of components and that Ndc80/Nuf2-like proteins are universal in eukaryotic division

"Wild worship of a lost and buried past" : enchanted archaeologies and the cult of Kata, 1908–1924

Histories of archaeology traditionally traced the progress of the modern discipline as the triumph of secular disenchanted science over pre-modern, enchanted, world-views. In this article I complicate and qualify the themes of disenchantment and enchantment in archaeological histories, presenting an analysis of how both contributed to the development of scienti c theory and method in the earliest decades of the twentieth century. I examine the interlinked biographies of a group who created a joke religion called “The Cult of Kata”. The self-described “Kataric Circle” included notable archaeologists Harold Peake, O.G.S. Crawford and Richard Lowe Thompson, alongside classicists, musicians, writers and performing artists. The cult highlights the connections between archaeology, theories of performance and the performing arts – in particular theatre, music, folk dance and song. “Wild worship” was linked to the consolidation of collectivities facilitating a wide variety of scienti c and artistic projects whose objectives were all connected to dreams of a future utopia. The cult parodied archaeological ideas and methodologies, but also supported and expanded the development of eld survey, mapping and the interpretation of archaeological distribution maps. The history of the Cult of Kata shows how taking account of the unorthodox and the interdisciplinary, the humorous and the recreational, is important within generously framed approaches to histories of the archaeological imagination. The work of the Kataric Circle is not best understood as the relentless progress of disenchanted modern science. It suggests a more complicated picture in which dynamics of enchantment and disenchantment stimulate and discipline the imagination simultaneously. I conclude with a reexamination of the politics of an emphasis on playfulness and enchantment