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Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Abstract (Expand)

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in … vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Authors: L. M. Bartos, S. V. Kirchleitner, Z. I. Kolabas, S. Quach, A. Beck, J. Lorenz, J. Blobner, S. A. Mueller, S. Ulukaya, L. Hoeher, I. Horvath, K. Wind-Mark, A. Holzgreve, V. C. Ruf, L. Gold, L. H. Kunze, S. T. Kunte, P. Beumers, H. E. Park, M. Antons, A. Zatcepin, N. Briel, L. Hoermann, R. Schaefer, D. Messerer, P. Bartenstein, M. J. Riemenschneider, S. Lindner, S. Ziegler, J. Herms, S. F. Lichtenthaler, A. Erturk, J. C. Tonn, L. von Baumgarten, N. L. Albert, M. Brendel

Date Published: 27th Oct 2023

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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