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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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