Biology subjects

Snellinx, A.

Publications and source records attributed to Snellinx, A..

7 recordsLinked to original sources

bioRxiv2025

The Alzheimer's therapeutic Lecanemab induces an amyloid-clearing program in microglia

Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-A{beta} antibody, mediates amyloid clearance by triggering effector functions in the microglia. Using a human microglia xenograft model, we show that Lecanemab significantly reduces A{beta} pathology and associated neuritic damage, while neither Fc-inactivated Lecanemab nor microglia deficiency elicit this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon gamma genes, and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting A{beta} clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through Fc fragment, providing critical insights for optimizing anti-amyloid therapies in AD.

neuroscience↗

bioRxiv2025

Divergent Effects of APOE3 and APOE4 Human Astrocytes on Key Alzheimer's Disease Hallmarks in Chimeric Mice

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimers disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to A{beta} plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate A{beta} pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to A{beta} pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around A{beta} plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to A{beta} pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.

neuroscience↗

bioRxiv2024

A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases

BackgroundRecent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. MethodsWe developed the hCSF1Bdes mouse line suitable as new transplantation model available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additional we crossed this model with two humanized App KI mice, the AppHu and the AppSAA . Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimers disease. ResultsOur results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore we confirmed the multipronged response of microglia in the context of Alzheimers disease. The hCSF1Bdes and the crosses with the Alzheimers disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. Conclusionthe hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.

neuroscience↗

bioRxiv2022

Deep proteomic analysis of human microglia and model systems reveal fundamental biological differences of in vitro and ex vivo cells

Using high resolution quantitative mass spectrometry, we have generated the most comprehensive human and mouse microglia proteomic datasets to date, consisting of over 11,000 proteins across all six microglia groups. Microglia from different sources share a core protein signature of over 5600 proteins, yet fundamental differences are observed between species and culture conditions, indicating limitations for human disease modelling in mouse or in in vitro cultures of microglia. Mouse ex vivo microglia show important differences at the proteome level such as differential expression of inflammation and Alzheimers Disease associated proteins. We identify a tenfold difference in the protein content of ex vivo and in vitro cells and significant proteome differences associated with protein synthesis, metabolism, microglia marker expression and environmental sensors. Culturing microglia induces rapidly increased growth, protein content and inflammatory protein expression. These changes can be restored by engrafting in vitro cells into the brain, with xenografted hESC-derived microglia closely resembling microglia from human brain. This data provides an important resource for the field and highlights important considerations needed when using model systems to study human physiology and pathology of microglia.

neuroscience↗

bioRxiv2022

Long noncoding RNA MEG3 activates neuronal necroptosis in Alzheimer's disease

Abstract/SummaryNeuronal cell loss is a defining feature of Alzheimers disease (AD), but it remains unclear how neurons die and how this relates to other defining characteristics of the disease1. Existing in vivo AD models only partially recapitulate the neuropathology of AD with very mild or no neuronal cell loss. Here we demonstrate that human neurons xenografted in mouse brain exposed to amyloid pathology develop sarkosyl-insoluble tau filaments, positive Gallyas silver staining, release phosphorylated tau (P-tau181) into the blood, and display considerable neuronal cell loss, providing a model for the induction of full Tau pathology by simple exposure to amyloid pathology in AD. The alterations are specific to human neurons and contrast with the mild effects exhibited in mouse neurons. A core transcriptional program in the human neurons is characterized by strong upregulation of MEG3, a neuron-specific long noncoding RNA. MEG3 is also strongly upregulated in neurons from AD patients in situ. MEG3 expression alone is sufficient to induce necroptosis in human neurons in vitro. Orally administered small molecule receptor-interacting protein (RIP) kinase -1 and -3 inhibitors rescued the neuronal cell loss in this novel AD model. Thus, xenografted human neurons are uniquely sensitive to amyloid pathology, recapitulate all the defining neuropathological features of AD, and ultimately die by necroptosis.

neuroscience↗

bioRxiv2020

Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

BackgroundIncreasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimers disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. MethodsTo address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. ResultsXenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimers chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. ConclusionIn sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimers disease.

neuroscience↗

bioRxiv2019

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

The linear cause-consequence relationship linking amyloid-{beta} peptide (A{beta}) accumulation to neuronal dysfunction in Alzheimer disease (AD) is gradually replaced by the concept that A{beta} initiates complex inflammatory-like cellular alterations that progressively become A{beta} independent and lead to brain dyshomeostasis. Little is known about the pathophysiology of this cellular phase of AD. We use here two orthogonal technologies, Spatial Transcriptomics and in situ sequencing, to analyse the transcriptome changes in cells in the amyloid-{beta} plaque niche in a knock-in mouse model for AD. We identify a multicellular co-expressed gene network of 57 Plaque-Induced Genes (PIGs) that define a series of co-ordinated and spatially restricted microglia, astroglia and oligodendrocyte responses to progressing amyloid plaques encompassing complement, oxidative stress and inflammation. A separate oligodendrocyte network suggests abnormal myelination. Spatial Transcriptomics provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.

neuroscience↗