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5 Publications visible to you, out of a total of 5
Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Abstract (Expand)

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-<i>GRN</i>). Multiple therapeutic … strategies are in clinical development to restore PGRN 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-<i>GRN</i>, namely, <i>Grn</i> knockout and <i>GrnxTmem106b</i> double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-<i>GRN</i>-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured 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 ameliorate FTLD-<i>GRN</i> 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-<i>GRN</i> and potentially other CNS disorders.

Authors: Marvin Reich, Matthew J Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H Suh, Thomas Sandmann, Mihalis S Kariolis, Sarah L DeVos, Joseph W Lewcock, Dominik Paquet, Anja Capell, Gilbert Di Paolo, Christian Haass

Date Published: 5th Jun 2024

Publication Type: Journal

Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging.

Abstract (Expand)

Age-related decline in brain endothelial cell (BEC) function contributes critically to neurological disease. Comprehensive atlases of the BEC transcriptome have become available, but results from … proteomic profiling are lacking. To gain insights into endothelial pathways affected by aging, we developed a magnetic-activated cell sorting-based mouse BEC enrichment protocol compatible with proteomics and resolved the profiles of protein abundance changes during aging. Unsupervised cluster analysis revealed a segregation of age-related protein dynamics with biological functions, including a downregulation of vesicle-mediated transport. We found a dysregulation of key regulators of endocytosis and receptor recycling (most prominently Arf6), macropinocytosis and lysosomal degradation. In gene deletion and overexpression experiments, Arf6 affected endocytosis pathways in endothelial cells. Our approach uncovered changes not picked up by transcriptomic studies, such as accumulation of vesicle cargo and receptor ligands, including Apoe. Proteomic analysis of BECs from Apoe-deficient mice revealed a signature of accelerated aging. Our findings provide a resource for analysing BEC function during aging.

Authors: K. Todorov-Volgyi, J. Gonzalez-Gallego, S. A. Muller, N. Beaufort, R. Malik, M. Schifferer, M. I. Todorov, D. Crusius, S. Robinson, A. Schmidt, J. Korbelin, F. Bareyre, A. Erturk, C. Haass, M. Simons, D. Paquet, S. F. Lichtenthaler, M. Dichgans

Date Published: 22nd Apr 2024

Publication Type: Journal

Distinct molecular profiles of skull bone marrow in health and neurological disorders.

Abstract (Expand)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that … the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.

Authors: Zeynep Ilgin Kolabas, Louis B Kuemmerle, Robert Perneczky, Benjamin Förstera, Selin Ulukaya, Mayar Ali, Saketh Kapoor, Laura M Bartos, Maren Büttner, Ozum Sehnaz Caliskan, Zhouyi Rong, Hongcheng Mai, Luciano Höher, Denise Jeridi, Muge Molbay, Igor Khalin, Ioannis K Deligiannis, Moritz Negwer, Kenny Roberts, Alba Simats, Olga Carofiglio, Mihail I Todorov, Izabela Horvath, Furkan Ozturk, Selina Hummel, Gloria Biechele, Artem Zatcepin, Marcus Unterrainer, Johannes Gnörich, Jay Roodselaar, Joshua Shrouder, Pardis Khosravani, Benjamin Tast, Lisa Richter, Laura Díaz-Marugán, Doris Kaltenecker, Laurin Lux, Ying Chen, Shan Zhao, Boris-Stephan Rauchmann, Michael Sterr, Ines Kunze, Karen Stanic, Vanessa W Y Kan, Simon Besson-Girard, Sabrina Katzdobler, Carla Palleis, Julia Schädler, Johannes C Paetzold, Sabine Liebscher, Anja E Hauser, Özgün Gökçe, Heiko Lickert, Hanno Steinke, Corinne Benakis, Christian Braun, Celia P Martinez-Jimenez, Katharina Buerger, Nathalie L Albert, Günter Höglinger, Johannes Levin, Christian Haass, Anna Kopczak, Martin Dichgans, Joachim Havla, Tania Kümpfel, Martin Kerschensteiner, Martina Schifferer, Mikael Simons, Arthur Liesz, Natalie Krahmer, Omer A Bayraktar, Nicolai Franzmeier, Nikolaus Plesnila, Suheda Erener, Victor G Puelles, Claire Delbridge, Harsharan Singh Bhatia, Farida Hellal, Markus Elsner, Ingo Bechmann, Benjamin Ondruschka, Matthias Brendel, Fabian J Theis, Ali Ertürk

Date Published: 17th Aug 2023

Publication Type: Journal

Signatures of glial activity can be detected in the CSF proteome.

Abstract (Expand)

Single-cell transcriptomics has revealed specific glial activation states associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. While these … findings may eventually lead to new therapeutic opportunities, little is known about how these glial responses are reflected by biomarker changes in bodily fluids. Such knowledge, however, appears crucial for patient stratification, as well as monitoring disease progression and treatment responses in clinical trials. Here, we took advantage of well-described mouse models of beta-amyloidosis and alpha-synucleinopathy to explore cerebrospinal fluid (CSF) proteome changes related to their respective proteopathic lesions. Nontargeted liquid chromatography-mass spectrometry revealed that the majority of proteins that undergo age-related changes in CSF of either mouse model were linked to microglia and astrocytes. Specifically, we identified a panel of more than 20 glial-derived proteins that were increased in CSF of aged beta-amyloid precursor protein- and alpha-synuclein-transgenic mice and largely overlap with previously described disease-associated glial genes identified by single-cell transcriptomics. Our results also show that enhanced shedding is responsible for the increase of several of the identified glial CSF proteins as exemplified for TREM2. Notably, the vast majority of these proteins can also be quantified in human CSF and reveal changes in Alzheimer's disease cohorts. The finding that cellular transcriptome changes translate into corresponding changes of CSF proteins is of clinical relevance, supporting efforts to identify fluid biomarkers that reflect the various functional states of glial responses in cerebral proteopathies, such as Alzheimer's and Parkinson's disease.

Authors: T. Eninger, S. A. Muller, M. Bacioglu, M. Schweighauser, M. Lambert, L. F. Maia, J. J. Neher, S. M. Hornfeck, U. Obermuller, G. Kleinberger, C. Haass, P. J. Kahle, M. Staufenbiel, L. Ping, D. M. Duong, A. I. Levey, N. T. Seyfried, S. F. Lichtenthaler, M. Jucker, S. A. Kaeser

Date Published: 14th Jun 2022

Publication Type: Journal

Fibrillar Abeta triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.

Abstract (Expand)

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. … Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid beta (Abeta) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Abeta Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Abeta deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Abeta, rather than dystrophic neurites, suggesting that fibrillar Abeta may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.

Authors: L. Sebastian Monasor, S. A. Muller, A. V. Colombo, G. Tanrioever, J. Konig, S. Roth, A. Liesz, A. Berghofer, A. Piechotta, M. Prestel, T. Saito, T. C. Saido, J. Herms, M. Willem, C. Haass, S. F. Lichtenthaler, S. Tahirovic

Date Published: 8th Jun 2020

Publication Type: Journal

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