Biology subjects

Zielonka, M.

Publications and source records attributed to Zielonka, M..

4 recordsLinked to original sources

bioRxiv2026

Glial subcellular specialisation resolved with high resolution spatial transcriptomics

Cells in the brain have complex structures with extended processes. This complex morphology supports diverse specialized functions in health and disease, and specifically, cell processes appear to be critical for cellular integration and signalling. Here, we developed a new spatial averaging framework to recover and interrogate molecular phenotypes of glial processes in spatial transcriptomics (ST) data. We characterised cell type specific signatures associated with processes of astrocytes and microglia in both mouse and human brain tissue. Astrocytic processes were enriched for transcripts related to neuronal support relative to their soma, while microglial processes preferentially expressed genes linked to specific microglial states. When investigated in tissue from brains with Alzheimers Disease (AD) pathology, we found that local amyloid-{beta} pathology was associated with subcellular differences in transcriptomes in both an amyloid-{beta} mouse model and human AD patient tissue. Specifically, astrocytic and microglial processes oriented toward amyloid-{beta} plaques exhibited distinct molecular changes in comparison to processes extending away into plaque free areas, suggesting polarized glial responses to pathology. Our work thus outlines a general method for the selective characterisation of transcriptomics of glial processes in mouse and human ST data and provides evidence for differential transcriptomic responses between the soma and processes of glia in health and disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/737168v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@157455corg.highwire.dtl.DTLVardef@8ac0a2org.highwire.dtl.DTLVardef@16ccbf5org.highwire.dtl.DTLVardef@1c24cd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

The Alzheimer's disease neurodegenerative cascade reconstructed in human L2/3 excitatory neurons

Identifying the molecular cascade underlying neuronal degeneration in Alzheimers disease has been hampered by cellular heterogeneity and the limitations of donor-level classification. By integrating 851,682 cortical layer 2 and 3 excitatory neuron transcriptomes from 557 individuals across four independent snRNA-seq datasets of the human prefrontal cortex, we reconstruct neuronal degeneration as a continuous, stage-resolved transcriptional trajectory. Ordering neurons by collective pathological burden and clinical manifestation reveals that degeneration unfolds asynchronously within individual brains. Neurons in a single brain can simultaneously occupy early, intermediate, and late pathological states, a continuum entirely obscured by conventional approaches. The trajectory captures discrete transcriptional inflection points defining successive stages of vulnerability linked to development of neuropathology. Systematic analysis of the complete human kinome and phosphatome along this trajectory identifies a temporal hierarchy of phosphorylation dysregulation which collectively creates a permissive environment for tau pathology to escalate, defining stage-specific molecular nodes in the degenerative cascade.

neuroscience↗

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↗

bioRxiv2023

Applying high-resolution spatial transcriptomics to characterise the amyloid plaque cell niche in Alzheimer's Disease

The amyloid plaque cell niche is a pivotal hallmark of Alzheimers disease (AD). Where early spatial transcriptomics (ST) technologies have provided valuable information on transcriptomic alterations in the small tissue domains overlaying with amyloid plaques, they lacked cellular resolution. Here we compare two novel high-resolution ST platforms, CosMx and Stereo-seq, in their ability to characterize the cellular response in the amyloid plaque niche in an AD mouse model. Combining the results from both techniques empowered us to survey the highly variable microglial-astrocytic response across the amyloid plaque micro-environment and provided a first insight into how these responses could relate to neuronal transcriptomic alterations. This pilot study demonstrates the great potential of high-resolution ST, while simultaneously highlighting limitations that, when addressed, will unleash the full power of these techniques to map the progression of molecular and cellular changes in the brains of AD patients.

neuroscience↗