TY  - JOUR
AU  - Eninger, Timo
AU  - Müller, Stephan A.
AU  - Bacioglu, Mehtap
AU  - Schweighauser, Manuel
AU  - Lambert, Marius
AU  - Maia, Luis F.
AU  - Neher, Jonas
AU  - Hornfeck, Sarah M
AU  - Obermüller, Ulrike
AU  - Kleinberger, Gernot
AU  - Haass, Christian
AU  - Kahle, Philipp
AU  - Staufenbiel, Matthias
AU  - Ping, Lingyan
AU  - Duong, Duc M.
AU  - Levey, Allan I.
AU  - Seyfried, Nicholas T.
AU  - Lichtenthaler, Stefan
AU  - Jucker, Mathias
AU  - Kaeser, Stephan A.
TI  - Signatures of glial activity can be detected in the CSF proteome
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 119
IS  - 24
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2022-01184
SP  - e2119804119
PY  - 2022
AB  - 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 β-amyloidosis and α-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 β-amyloid precursor protein- and α-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.
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: metabolism
KW  - Animals
KW  - Biomarkers: cerebrospinal fluid
KW  - Cerebrospinal Fluid: metabolism
KW  - Gene Expression Profiling
KW  - Humans
KW  - Mice
KW  - Neuroglia: metabolism
KW  - Parkinson Disease: cerebrospinal fluid
KW  - Parkinson Disease: metabolism
KW  - Proteome: metabolism
KW  - Single-Cell Analysis
KW  - tau Proteins
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9214531
C6  - pmid:35666874
DO  - DOI:10.1073/pnas.2119804119
UR  - https://pub.dzne.de/record/164654
ER  -