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Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Karpagam Srinivasan1, Brad A Friedman2, Ainhoa Etxeberria1
1Department of Neuroscience, Genentech, Inc., South San Francisco, CA, USA.
Abstract:
Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
Insights
Human Alzheimer's disease (AD) microglia do not show the same activation profile as mouse models. Instead, human microglia exhibit aging-related changes and APOE upregulation, highlighting key differences in AD research.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Microglia, the brain's immune cells, exhibit a specific activation state (DAM) in Alzheimer's disease (AD) mouse models.
- This DAM profile is hypothesized to influence AD progression and risk.
Purpose of the Study:
- To investigate whether human AD microglia (HAM) share the DAM profile observed in mouse models.
- To characterize the transcriptomic landscape of microglia in human AD brains.
Main Methods:
- Development of a novel method for purifying cell types from frozen human cerebrocortical tissue for RNA-sequencing.
- Comparative analysis of HAM transcriptomes against DAM profiles and human aging signatures.
- Validation using whole-tissue and single-cell/nucleus RNA-seq datasets.
Main Results:
- Human AD microglia (HAM) profiles show minimal resemblance to the DAM profile from mouse models.
- HAM exhibit an enhanced human aging transcriptomic signature, alongside APOE upregulation and other disease-associated changes.
- The absence of a DAM response in human microglia appears specific to AD, not other neurodegenerative conditions.
Conclusions:
- Mouse models of AD do not accurately recapitulate the microglial activation state observed in human AD.
- Human microglia in AD display distinct molecular signatures related to aging and specific disease pathways.
- These findings underscore the importance of studying human tissues for understanding AD pathogenesis and developing targeted therapies.
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