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Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related
Renzo Mancuso1,2,3, Nicola Fattorelli4,5, Anna Martinez-Muriana4,5
1Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. renzo.mancuso@uantwerpen.vib.be.
Abstract:
Microglia are central players in Alzheimer's disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer's disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer's disease-related pathology, which should be taken into account in translational studies.
Insights
Human microglia transplanted into mouse models reveal complex responses to Alzheimer's disease pathology. These findings offer new insights into disease mechanisms and potential therapeutic targets for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial in Alzheimer's disease (AD) pathogenesis.
- Analyzing human microglial states is difficult due to biological variability and postmortem factors.
Purpose of the Study:
- To investigate human microglial responses to AD pathology in a controlled experimental setting.
- To identify distinct transcriptomic states of human microglia in response to amyloid pathology.
Main Methods:
- Generation of 138,577 single-cell expression profiles from human stem cell-derived microglia xenotransplanted into AppNL-G-F mice and wild-type controls.
- Analysis of microglial transcriptomic profiles to identify disease-associated states and responses to amyloid pathology.
Main Results:
- Xenografted human microglia exhibited disease-associated profiles and enhanced human leukocyte antigen (HLA) states, indicative of antigen presentation.
- A pro-inflammatory cytokine/chemokine cytokine response microglia (CRM) response to oligomeric amyloid-beta (Aβ) was observed.
- Genetic modifications (TREM2, APOE deletion/polymorphisms) and TREM2R47H expression differentially modulated microglial responses.
- Alzheimer's disease risk genes were differentially regulated across identified microglial cell states.
Conclusions:
- Human microglia adopt multiple transcriptomic states in response to AD-related amyloid pathology.
- These findings highlight the complexity of microglial responses in AD and are crucial for translational research.
- The study provides a valuable model for dissecting human microglial behavior in neurodegenerative disease contexts.
