Spatial proteomics reveals human microglial states shaped by anatomy and neuropathology
Dunja Mrdjen1, Meelad Amouzgar1, Bryan Cannon1
1Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA.
Abstract:
Microglia are implicated in aging, neurodegeneration, and Alzheimer's disease (AD). Traditional, low-plex, imaging methods fall short of capturing in situ cellular states and interactions in the human brain. We utilized Multiplexed Ion Beam Imaging (MIBI) and data-driven analysis to spatially map proteomic cellular states and niches in healthy human brain, identifying a spectrum of microglial profiles, called the microglial state continuum (MSC). The MSC ranged from senescent-like to active proteomic states that were skewed across large brain regions and compartmentalized locally according to their immediate microenvironment. While more active microglial states were proximal to amyloid plaques, globally, microglia significantly shifted towards a, presumably, dysfunctional low MSC in the AD hippocampus, as confirmed in an independent cohort (n=26). This provides an in situ single cell framework for mapping human microglial states along a continuous, shifting existence that is differentially enriched between healthy brain regions and disease, reinforcing differential microglial functions overall.
Insights
Researchers mapped microglial states in the human brain using advanced imaging. They discovered a spectrum of microglial profiles, shifting towards dysfunction in Alzheimer's disease (AD) hippocampus.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia play crucial roles in brain aging, neurodegeneration, and Alzheimer's disease (AD).
- Existing imaging techniques struggle to capture the complex in situ cellular states and interactions within the human brain.
Purpose of the Study:
- To spatially map proteomic cellular states and niches of microglia in the healthy human brain.
- To characterize the microglial state continuum (MSC) and its distribution across brain regions and microenvironments.
- To investigate shifts in microglial states in Alzheimer's disease (AD) hippocampus.
Main Methods:
- Multiplexed Ion Beam Imaging (MIBI) was employed to spatially map proteomic profiles.
- Data-driven analysis was used to identify and characterize the microglial state continuum (MSC).
- Proteomic profiles were analyzed in both healthy and AD human brain cohorts.
Main Results:
- A spectrum of microglial profiles, the microglial state continuum (MSC), was identified, ranging from senescent-like to active states.
- Microglial states were differentially distributed across brain regions and compartmentalized based on local microenvironments.
- Active microglial states were found proximal to amyloid plaques, while a shift towards a dysfunctional, low MSC was observed in the AD hippocampus.
- This shift in the AD hippocampus was confirmed in an independent cohort.
Conclusions:
- The study provides an in situ single-cell framework for mapping human microglial states.
- Microglial states exist on a continuous spectrum and shift differentially between healthy brain regions and in disease states like AD.
- These findings reinforce the concept of differential microglial functions in health and disease.
