Biology subjects

Obst, J.

Publications and source records attributed to Obst, J..

4 recordsLinked to original sources

bioRxiv2025

SHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC-derived model

Genetic and functional studies strongly implicate microglia in the pathology of Alzheimers disease (AD). The Triggering Receptor Expressed on Myeloid cells 2 (TREM2) pathway is an important functional regulator of microglia in AD, promoting phagocytosis of apoptotic cells, debris and pathogenic proteins including amyloid beta (A{beta}). Additionally, genome-wide association studies have identified risk bearing polymorphisms in several members of the pathway including INPP5D, encoding the inositol phosphatase SHIP1. Recent studies utilising in vitro macrophage and microglia models and preclinical mouse models have identified a role for SHIP1 in both modulating TREM2 signalling and modulating neurotoxic microglial activation. In this study, we characterised the role of SHIP1 in regulating TREM2 signalling and global microglial functions using human induced pluripotent stem cell (hiPSC)-derived macrophages as a physiologically-relevant in vitro model of microglia. Isogenic parent and SHIP1 knockout (SHIP1 KO) lines were generated and macrophage phenotype and functions investigated. Knocking out SHIP1 was associated with a decreased expression of the lipopolysaccharide (LPS) co-receptor CD14, which translated to lower secretion of pro-inflammatory cytokines on stimulation with LPS. Additionally, SHIP1 KO hiPSC-derived macrophages showed decreased signalling upon TREM2 stimulation, which was further reflected in a reduced level of phagocytosis of apoptotic neurons compared to the parental line. The observed attenuated TREM2 signalling did not correspond to decreased TREM2 protein levels nor increased shedding of the receptor. Examination of macrophage scavenger receptor expression revealed reduced cell surface levels of CD163 and CD206 involved in resolution of inflammation but increased levels of the phagocytic receptor MerTK, while morphological analysis revealed a less amoeboid activated phenotype and increased adhesion. Taken together, our data indicates that SHIP1 plays a key role in regulating global macrophage functions in addition to modulating TREM2 signalling and inflammation.

immunology↗

bioRxiv2023

Multiple Pleistocene refugia for Arctic White Heather (Cassiope tetragona) supported by population genomics analyses of contemporary and Little-Ice-Age samples

AimArctic plants survived the Pleistocene glaciations in unglaciated refugia, but the number of these refugia is often unclear. We use high-resolution genomic data from present-day and Little-Ice-Age populations of Arctic White Heather (Cassiope tetragona) to re-evaluate the biogeography of this species and determine whether it had multiple independent refugia or a single refugium in Beringia. LocationCircumpolar Arctic and Coastal British Columbia (BC) alpine TaxonCassiope tetragona L., subspecies saximontana and tetragona, outgroup C. mertensiana (Ericaceae) MethodsWe built genotyping-by-sequencing (GBS) libraries using Cassiope tetragona tissue from 36 Arctic locations, including two [~]250-500-year-old populations collected under glacial ice on Ellesmere Island, Canada. We assembled a de novo GBS reference and called variants in dDocent. Population structure, genetic diversity, and demography were inferred from PCA, ADMIXTURE, fastsimcoal2, SplitsTree, and several population genomics statistics. ResultsPopulation structure analyses identified 4-5 clusters that align with geographic locations. Nucleotide diversity was highest in Beringia and decreased eastwards across Canada. Demographic coalescent analysis of the site-frequency-spectrum dated the following splits from Alaska: BC subspecies saximontana (6 mya), Russia (1.5 mya), Europe (>300-600 kya), Greenland (100 kya). Northern Canada populations appear to be from the current interglacial (7-9 kya). Genetic variants from Alaska appeared more frequently in present-day than historic plants on Ellesmere Island. ConclusionsDemographic analyses show BC, Alaska, Russia, Europe, and Greenland all had separate refugia during the last major glaciations. Northern Canadian populations appear to be founded during the current interglacial with genetic contributions from Alaska, Europe, and Greenland. On Ellesmere Island, there is evidence for continued, recent gene flow with foreign variants introduced in the last 250-500 years. These results suggest that a re-analysis of other Arctic species with shallow population structure using higher resolution genomic markers and demographic analyses may help reveal deeper structure and other circumpolar glacial refugia.

genomics↗

bioRxiv2021

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology

The sustained proliferation of microglia is a key hallmark of Alzheimers disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased {beta}gal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of A{beta} and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early A{beta} pathology in AD.

neuroscience↗

bioRxiv2020

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimers disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

neuroscience↗