Biology subjects

Nuscher, B.

Publications and source records attributed to Nuscher, B..

5 recordsLinked to original sources

bioRxiv2026

A reproducible human brain tissue model to study physiological and disease-associated microglia phenotypes

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions under physiological and pathological conditions. However, harnessing this potential is impaired by low reproducibility, maturity, or cell-type diversity of existing models. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a 3D cortical brain tissue model (3BTM) containing neurons, astrocytes, and microglia with high reproducibility, maturity, and viability. 3BTMs show morphological, functional, and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions, and gene expression. Importantly, when engineered to model Alzheimers disease pathology, 3BTMs recapitulate key disease hallmarks including amyloid deposition, increased phospho-Tau levels, and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Together, our model offers unprecedented possibilities for studying physiological and pathological states of human brain tissue and translational applications.

neuroscience↗

bioRxiv2025

Loss of the Parkinson's disease-associated protein DJ-1 impacts dopamine metabolism in astrocytes

The selective loss of dopaminergic neurons in the substantia nigra is a hallmark of Parkinsons disease (PD), yet the contribution of glial cells to this vulnerability is not fully understood. Studies in rodent models suggest that astrocytes can take up and metabolize dopamine (DA), potentially protecting neurons by detoxifying reactive DA metabolites via glutathione S-transferase mu 2 (GSTM2) release. However, these mechanisms remain underexplored in human systems, particularly in the context of PD. Here, we used CRISPR-engineered iPSC-derived human astrocytes with a PD-linked DJ-1 mutation and isogenic controls to investigate astrocytic DA metabolism. Upon DA exposure, control astrocytes upregulated quinone-reducing enzymes NAD(P)H quinone dehydrogenase 1 (NQO1) and GSTM2, whereas DJ-1 mutant astrocytes failed to adaptively respond. In addition, only control astrocytes presented with increased DA quinone products upon DA exposure, not DJ-1 mutants. These results demonstrate astrocytic DA handling being disrupted in DJ-1-linked PD, implicating astroglial dysfunction as an important contributor to PD pathogenesis and potential target for therapeutic intervention.

neuroscience↗

bioRxiv2025

Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques

Anti-amyloid {beta}-peptide (A{beta}) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimers disease. Efficient amyloid plaque clearance has been proven in clinical trials testing anti-A{beta} antibodies, with the impact on cognitive endpoints correlating with the extent of plaque removal. However, treatment is associated with adverse side-effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-A{beta} antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-A{beta} treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with anti-A{beta} antibody from 4-8 months of age. Long-term treatment with anti-A{beta} results in a robust and dose-dependent removal of amyloid plaque pathology, with a higher efficiency for removing diffuse over dense-core plaques. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and -Synuclein, as well as immune cell related proteins. Bulk RNA-seq revealed a dose-dependent decrease in brain-wide disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering receptor of myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around remaining plaques remains high regardless of treatment dose. In addition, microglia surrounding remaining plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen presenting and immune signalling proteins. These findings demonstrate that long-term chronic anti-A{beta} mediated removal of A{beta} leads to a dose dependent decrease in brain-wide microglial DAM activation and neurodegeneration, while microglia at residual plaques display a combined DAM and antigen presenting phenotype that suggests a continued treatment response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/645950v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6d1a49org.highwire.dtl.DTLVardef@d8c14dorg.highwire.dtl.DTLVardef@7ae330org.highwire.dtl.DTLVardef@1d96cc3_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: Schematic overview of the effects of chronic long-term anti-A treatment in APP-SAA mice Schematic was created with BioRender.com C_FIG

neuroscience↗

bioRxiv2023

Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD-GRN, namely Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN associated disease pathologies including severe motor function deficits, aberrant TDP-43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel human in vitro model using co-cultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders. One sentence summaryPeripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRN models.

neuroscience↗

bioRxiv2021

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

neuroscience↗