Dataset Information

Proteome Profiling in Cerebrospinal Fluid Reveals Novel Biomarkers of Alzheimerâ€™s Disease

ABSTRACT: Neurodegenerative diseases are a growing burden and there is an urgent need for better biomarkers for diagnosis, prognosis and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimerâ€™s disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems-wide changes of CSF protein levels that accompany AD. Here we present a highly reproducible mass spectrometry (MS)-based proteomics workflow for the in-depth analysis of CSF from minimal sample amounts. From three independent studies (>200 individuals), we characterize differences in proteins by AD status (>1,000 proteins, CV<20%). Proteins with previous links to neurodegeneration such as tau, SOD1 and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimerâ€™s disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our and a recent report (bioRxiv.org doi.org/10.1101/806752). Successful reclassification of individual patients and a machine learning model suggests clinical utility of our proteomic signature.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Matthias Mann

PROVIDER: MSV000088649 | MassIVE | Thu Jan 06 10:41:00 GMT 2022

SECONDARY ACCESSION(S): PXD016278

REPOSITORIES: MassIVE

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Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease.

Bader Jakob M JM Geyer Philipp E PE Müller Johannes B JB Strauss Maximilian T MT Koch Manja M Leypoldt Frank F Koertvelyessy Peter P Bittner Daniel D Schipke Carola G CG Incesoy Enise I EI Peters Oliver O Deigendesch Nikolaus N Simons Mikael M Jensen Majken K MK Zetterberg Henrik H Mann Matthias M

Molecular systems biology 20200601 6

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems-wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)-based proteomics workf ...[more]

PMID: 32485097

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Project description:Alzheimer’s disease (AD) is a major neurodegenerative disease characterized by extracellular amyloid β (Aβ) plaques and intracellular hyperphosphorylated tau (P-tau). Increasing evidence indicates that extracellular vesicles (EVs) play an important role in AD pathogenesis. We previously reported that the choroid plexus epithelial (CPE) cells, present at the interface between blood and cerebrospinal fluid (CSF), show increased secretion of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-derived EVs in AD pathogenesis. We observed increased EV levels in the CSF of 7 weeks old transgenic APP/PS1 mice, correlating with higher Aβ CSF levels at this age, while levels normalized with age. To study whether the elevated Aβ CSF levels might be responsible for this increase, mice were intracerebroventricularly (icv) injected with Aβ oligomers (AβO) which revealed a significant increase in the amount of CD9 and CD81 positive EVs in the CSF. The importance of the CPE cells as EV source was shown by in vitro analysis of AβO stimulated primary CPE cells and in vivo analysis of the CP by transmission electron microscopy (TEM). Evaluation of EV marker immunostaining, both from AβO icv injected mice and APP/PS1 mice, confirmed the upregulation of EV biogenesis in the CP. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures (MCC) whereas proteome analysis revealed the presence of complement protein C3, amongst other inflammatory proteins. Additionally, we could show for the first time that AβO induce an upregulation of C3 in CPE cells. These data highlight the CP and CP-derived, C3-containing EVs as novel players in the emerging importance of the complement pathway in the pathogenesis of AD. Strikingly, inhibition of EV production using GW4869 resulted in protection against the AβO-induced cognitive decline. In conclusion, our results show that intraventricular AβO induce both C3 activation and EV secretion by the CP and that these EVs contain pro-inflammatory molecules, including C3, which play a role in neuroinflammation and loss of cognition. This suggests that inhibition of EV production by the CP might be an interesting therapeutic approach to be explored in the prevention or treatment of AD.