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Microglia protein profiles in CSF across Alzheimer's disease clinical stages
Elena-Raluca Blujdea1, Pieter van Bokhoven2,3, Pamela V Martino-Adami4
1Neurochemistry Laboratory and Biobank, Department of Laboratory Medicine, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. e.blujdea@amsterdamumc.nl.
Abstract:
Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.
Insights
Cerebrospinal fluid (CSF) microglia profiling reveals distinct protein changes across Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Biomarker Discovery
Background:
- Microglia play a crucial role in Alzheimer's disease (AD) pathology from early stages.
- Cerebrospinal fluid (CSF) microglia profiling offers potential for AD treatment monitoring.
Purpose of the Study:
- To analyze CSF microglia protein profiles across different clinical stages of AD.
- To identify stage-specific protein signatures and correlate them with transcriptomic data.
- To develop a protein panel for staging AD.
Main Methods:
- Analysis of CSF microglia-related proteins in two cohorts (n=834) spanning unimpaired, preclinical, and dementia AD stages.
- Enrichment analyses to identify immune processes.
- Alignment of in vivo protein profiles with ex vivo microglial transcriptomic signatures.
Main Results:
- Identified 109 dysregulated microglia-related proteins.
- Preclinical AD showed innate immune and cellular recruitment changes; AD dementia showed adaptive immunity and macrophage responses.
- An 18-protein panel distinguished preclinical from dementia stages.
- Transcriptomic signatures were not stage-specific but spanned both preclinical and dementia stages.
Conclusions:
- CSF microglia profiling provides insights into AD staging and microglia dynamics.
- Microglia-based biomarkers hold promise for AD staging and monitoring.
- Translational insights from transcriptomic to proteomic profiles are crucial for understanding AD progression.
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