Spatial proteomics of Alzheimer's disease-specific human microglial states
Dunja Mrdjen1, Bryan J Cannon1, Meelad Amouzgar1
1Department of Pathology, Stanford University, School of Medicine, Palo Alto, CA, USA.
Abstract:
Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.
Insights
Microglia, immune cells in the brain, show diverse protein profiles linked to aging and Alzheimer's disease (AD). This study maps these states in humans, revealing shifts in AD that could inform future treatments.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia play roles in brain aging, neurodegeneration, and Alzheimer's disease (AD).
- Existing low-plex protein imaging methods inadequately capture the complexity of human brain cellular states and interactions, unlike rodent models.
Purpose of the Study:
- To spatially map cellular states and microglial niches in cognitively normal human brains using multiplexed ion beam imaging.
- To identify a spectrum of proteomic microglial profiles and their associated molecular functions.
- To investigate regulatory shifts in immunologically active cells in AD tissues.
Main Methods:
- Multiplexed ion beam imaging (MIBI) was employed to spatially map cellular proteomic states in human brain tissue.
- Single-nuclei epigenetic analysis was performed orthogonally to complement proteomic findings.
- Proteomic trends and cellular states were analyzed across different brain regions and microenvironments.
Main Results:
- A spectrum of proteomic microglial profiles was identified, varying by immune activation states and compartmentalized by microenvironments.
- These proteomic trends were correlated with molecular functions through epigenetic analysis.
- Alzheimer's disease (AD) tissues showed distinct regulatory shifts in immunologically active cells, including altered expression of CD33, CD44, HLA-DR, P2RY12, and ApoE.
Conclusions:
- The study establishes an in situ, single-cell spatial proteomic framework for characterizing AD-specific microglial states.
- These findings highlight regional and microenvironmental influences on microglial heterogeneity in the human brain.
- The identified proteomic and epigenetic signatures provide insights into microglial dysfunction in AD pathogenesis.
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