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52 Publications visible to you, out of a total of 52
Identification and validation of a tear fluid-derived protein biomarker signature in patients with amyotrophic lateral sclerosis.

Abstract (Expand)

The diagnosis of Amyotrophic Lateral Sclerosis (ALS) remains challenging, particularly in early stages, where characteristic symptoms may be subtle and nonspecific. The development of disease-specific … and clinically validated biomarkers is crucial to optimize diagnosis. Here, we explored tear fluid (TF) as a promising ALS biomarker source, given its accessibility, anatomical proximity to the brainstem as an important site of neurodegeneration, and proven discriminative power in other neurodegenerative diseases. Using a discovery approach, we profiled protein abundance in TF of ALS patients (n = 49) and controls (n = 54) via data-independent acquisition mass spectrometry. Biostatistical analysis and machine learning identified differential protein abundance and pathways in ALS, leading to a protein signature. These proteins were validated by Western blot in an independent cohort (ALS n = 51; controls n = 52), and their discriminatory performance was assessed in-silico employing machine learning. 876 proteins were consistently detected in TF, with 106 differentially abundant in ALS. A six-protein signature, including CRYM, PFKL, CAPZA2, ALDH16A1, SERPINC1, and HP, exhibited discriminatory potential. We replicated significant differences of SERPINC1 and HP levels between ALS and controls across the cohorts, and their combination yielded the best in-silico performance. Overall, this investigation of TF proteomics in ALS and controls revealed dysregulated proteins and pathways, highlighting inflammation as a key disease feature, strengthening the potential of TF as a source for biomarker discovery.

Authors: Lena-Sophie Scholl, Antonia F Demleitner, Jenny Riedel, Seren Adachi, Lisa Neuenroth, Clara Meijs, Laura Tzeplaeff, Lucas Caldi Gomes, Ana Galhoz, Isabell Cordts, Christof Lenz, Michael Menden, Paul Lingor

Date Published: 2nd Sep 2025

Publication Type: Journal

Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.

Abstract (Expand)

Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been … proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid 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-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.

Authors: Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass

Date Published: 20th Aug 2025

Publication Type: Journal

Structural analyses define the molecular basis of clusterin chaperone function.

Abstract (Expand)

Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset … Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two disordered, hydrophobic peptide tails enable diverse activities. Resembling the substrate-binding regions of small heat-shock proteins, these sequences mediate clusterin's chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with conserved surface areas, the tail segments also participate in clusterin binding to cell surface receptors and cellular uptake. While contributing to lipoprotein formation, the hydrophobic tails remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipids in maintaining the solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.

Authors: Patricia Yuste-Checa, Alonso I Carvajal, Chenchen Mi, Sarah Paatz, F Ulrich Hartl, Andreas Bracher

Date Published: 8th Aug 2025

Publication Type: Journal

Privacy-preserving multicenter differential protein abundance analysis with FedProt.

Abstract (Expand)

Quantitative mass spectrometry has revolutionized proteomics by enabling simultaneous quantification of thousands of proteins. Pooling patient-derived data from multiple institutions enhances statistical … power but raises serious privacy concerns. Here we introduce FedProt, the first privacy-preserving tool for collaborative differential protein abundance analysis of distributed data, which utilizes federated learning and additive secret sharing. In the absence of a multicenter patient-derived dataset for evaluation, we created two: one at five centers from E. coli experiments and one at three centers from human serum. Evaluations using these datasets confirm that FedProt achieves accuracy equivalent to the DEqMS method applied to pooled data, with completely negligible absolute differences no greater than 4 × 10<sup>-12</sup>. By contrast, -log<sub>10</sub>P computed by the most accurate meta-analysis methods diverged from the centralized analysis results by up to 25-26.

Authors: Yuliya Burankova, Miriam Abele, Mohammad Bakhtiari, Christine von Toerne, Teresa K Barth, Lisa Schweizer, Pieter Giesbertz, Johannes R Schmidt, Stefan Kalkhof, Janina Müller-Deile, Peter A van Veelen, Yassene Mohammed, Elke Hammer, Lis Arend, Klaudia Adamowicz, Tanja Laske, Anne Hartebrodt, Tobias Frisch, Chen Meng, Julian Matschinske, Julian Späth, Richard Röttger, Veit Schwämmle, Stefanie M Hauck, Stefan F Lichtenthaler, Axel Imhof, Matthias Mann, Christina Ludwig, Bernhard Kuster, Jan Baumbach, Olga Zolotareva

Date Published: 11th Jul 2025

Publication Type: Journal

Soluble VCAM-1 May Serve as a Pharmacodynamic CSF Marker to Monitor BACE2 Activity in Non-Human Primates.

Abstract (Expand)

The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem … from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo, and no biomarker is available to monitor the extent of BACE2 inhibition in vivo, particularly in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes in non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small-molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130, and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD.

Authors: Sarah K Tschirner, Y Joy Yu Zuchero, Jennifer A Getz, Stephan A Müller, Karsten Nalbach, Matthew E Kennedy, Joseph W Lewcock, Stefan F Lichtenthaler

Date Published: 4th Jun 2025

Publication Type: Journal

Molecular insights into myelomeningocele via proteomic analysis of amniotic fluid.

Abstract (Expand)

Despite numerous studies on fetal therapy for myelomeningoceles (MMC), the pathophysiology of this malformation remains poorly understood. This study aimed to analyze the biochemical profile and proteome … of amniotic fluid (AF) supernatants from MMC fetuses to explore the prenatal pathophysiology. Biochemical analysis of 61 AF samples from MMC fetuses was compared with 45 healthy fetuses' samples. Proteome analysis was conducted in 18 MMC and 18 healthy singleton fetuses, and in 5 dichorionic pregnancies with MMC fetuses and their healthy co-twins. ELISA tests were used to validate proteome results. Biochemical analysis revealed anal incontinence in 37 % of MMC cases, absent in controls (p &lt; 0.0001). Proteomics identified 2453 quantified proteins with 39 significantly up-regulated and 10 down-regulated in the MMC group. Up-regulated proteins included ectodomains of CHL1, APLP1, SEZ6, SEZ6L, known targets of the protease BACE1. We explored the overlap of neonatal cerebrospinal fluid (CSF) and AF proteome and highlighted 411 proteins in common, mostly upregulated in MMC AF compared to controls. Our study thoroughly characterizes the AF proteome and reveals numerous proteins to be changed as a consequence of MMC. Many of these proteins are typical constituents of CSF. No difference in AF inflammation markers were observed between MMC and healthy fetuses. SIGNIFICANCE: This study provides good evidence that neuroepithelial destruction in MMC is independent of inflammation or presumed meconium toxicity.

Authors: Lucie Guilbaud, Kévin Roger, Andree Schmidt, Cerina Chhuon, Stephan Breimann, Joanna Lipecka, Sophie Dreux, Stephan A Müller, Michel Zérah, Jérôme Larghero, Jean-Marie Jouannic, Stefan F Lichtenthaler, Ida C Guerrera

Date Published: 20th Mar 2025

Publication Type: Journal

The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis.

Abstract (Expand)

The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimer's disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, … linked to AD risk, but the responsible protease in microglia is still unknown. Another microglial-expressed AD risk factor is catalytically inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and acts as a non-catalytic subunit of the metalloprotease ADAM17. A potential role in TREM2 proteolysis is not yet known. Using microglial-like BV2 cells, bone marrow-derived macrophages, and primary murine microglia, we identify iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss of iRhom2 increased TREM2 in cell lysates and at the cell surface and enhanced TREM2 signaling and microglial phagocytosis of the amyloid β-peptide (Aβ). This study establishes ADAM17 as a physiological TREM2 protease in microglia and suggests iRhom2 as a potential drug target for modulating TREM2 proteolysis in AD.

Authors: Georg Jocher, Gozde Ozcelik, Stephan A Müller, Hung-En Hsia, Miranda Lastra Osua, Laura I Hofmann, Marlene Aßfalg, Lina Dinkel, Xiao Feng, Kai Schlepckow, Michael Willem, Christian Haass, Sabina Tahirovic, Carl P Blobel, Stefan F Lichtenthaler

Date Published: 13th Mar 2025

Publication Type: Journal

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