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Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.
Elife. 2020 06 08; 9E

Abstract

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 β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ 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.

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Authors+Show Affiliations

Sebastian Monasor L
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University, Munich, Germany.
Müller SA
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Colombo AV
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Tanrioever G
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
König J
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Faculty of Chemistry, Technical University of Munich, Garching, Germany.
Roth S
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU, Munich, Germany.
Liesz A
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Berghofer A
Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University, Munich, Germany.
Piechotta A
Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle, Germany.
Prestel M
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU, Munich, Germany.
Saito T
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan. Department of Neurocognitive Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.
Saido TC
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan.
Herms J
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Willem M
Biomedical Center (BMC), Ludwig-Maximilians Universität München, Munich, Germany.
Haass C
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Biomedical Center (BMC), Ludwig-Maximilians Universität München, Munich, Germany.
Lichtenthaler SF
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University, Munich, Germany.
Tahirovic S
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsDisease Models, AnimalFemaleGene Knock-In TechniquesMaleMiceMice, TransgenicMicrogliaProteome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32510331

Citation

Sebastian Monasor, Laura, et al. "Fibrillar Aβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse Models." ELife, vol. 9, 2020.
Sebastian Monasor L, Müller SA, Colombo AV, et al. Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. Elife. 2020;9.
Sebastian Monasor, L., Müller, S. A., Colombo, A. V., Tanrioever, G., König, J., Roth, S., Liesz, A., Berghofer, A., Piechotta, A., Prestel, M., Saito, T., Saido, T. C., Herms, J., Willem, M., Haass, C., Lichtenthaler, S. F., & Tahirovic, S. (2020). Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. ELife, 9. https://doi.org/10.7554/eLife.54083
Sebastian Monasor L, et al. Fibrillar Aβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse Models. Elife. 2020 06 8;9 PubMed PMID: 32510331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. AU - Sebastian Monasor,Laura, AU - Müller,Stephan A, AU - Colombo,Alessio Vittorio, AU - Tanrioever,Gaye, AU - König,Jasmin, AU - Roth,Stefan, AU - Liesz,Arthur, AU - Berghofer,Anna, AU - Piechotta,Anke, AU - Prestel,Matthias, AU - Saito,Takashi, AU - Saido,Takaomi C, AU - Herms,Jochen, AU - Willem,Michael, AU - Haass,Christian, AU - Lichtenthaler,Stefan F, AU - Tahirovic,Sabina, Y1 - 2020/06/08/ PY - 2019/12/01/received PY - 2020/05/02/accepted PY - 2020/6/9/entrez PY - 2020/6/9/pubmed PY - 2021/2/23/medline KW - Alzheimer's disease KW - microglia KW - mouse KW - neuroinflammation KW - neuroscience KW - phagocytosis KW - proteomic signatures JF - eLife JO - Elife VL - 9 N2 - 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 β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/32510331/Fibrillar_Aβ_triggers_microglial_proteome_alterations_and_dysfunction_in_Alzheimer_mouse_models_ DB - PRIME DP - Unbound Medicine ER -