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Microglia Demonstrate Local Mixed Inflammation and a Defined Morphological Shift in an APP/PS1 Mouse Model
Olivia G Holloway1, Anna E King1, Jenna M Ziebell1
1Wicking Dementia Research and Education Centre, College of Health and Medicine, University of Tasmania, Tasmania, Australia.
Background:
Microglia are traditionally described as the immune cells of the brain and have an inflammatory role in Alzheimer's disease (AD). Microglial morphological and phenotypic shifts in AD have not been fully characterized; however, microglia are often described as either pro- or anti-inflammatory.
Objective:
To determine microglial if microglial morphology and phenotype changes with disease status.
Methods:
This study observed morphology through Iba1 immunohistochemistry on tissue sections encompassing the primary motor cortex and somatosensory barrel fields. Immunohistochemistry for pro-inflammatory markers: CD14 and CD40; and anti-inflammatory markers: CD16 and TREM2, was performed at 3, 6, and 12 months of age which correlated with pre-plaque, onset, and significant plaque load in APP/PS1 brains (n = 6) and compared to age-matched littermate controls (n = 6).
Results:
Microglia demonstrated a defined morphological shift with time. Deramified morphologies increased in the APP/PS1, at both 6 months (p < 0.0001) and 12 months (p < 0.0001). At 12 months, there were significantly lower numbers of ramified microglia (p < 0.001). Results indicated that microglia have a heterogenic marker immunoreactivity as CD16, TREM2, and CD40 were associated with an activated morphology at the same time points. All inflammatory markers were significantly upregulated at 12 months in the APP/PS1 mice (TREM2 (F (2,30) = 10.75, p = 0.0003), CD40 (F (2,30) = 15.86, p < 0.0001), CD14 (F (2,30) = 6.84, p = 0.0036), and CD16 (F (2,30) = 3.026, p = 0.0635)).
Conclusion:
Our data indicate that pro- and anti-inflammatory factors of microglia occur in APP/PS1 mice.
Insights
Microglia in Alzheimer's disease (AD) models show significant morphological changes and express both pro- and anti-inflammatory markers. These shifts correlate with disease progression, indicating a complex microglial response in AD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia, the brain's immune cells, are implicated in Alzheimer's disease (AD) pathogenesis, traditionally viewed with an inflammatory role.
- The dynamic morphological and phenotypic alterations of microglia in AD remain incompletely understood, with ongoing debate on their pro- or anti-inflammatory nature.
Purpose of the Study:
- To investigate the changes in microglial morphology and phenotype in relation to disease progression in a mouse model of Alzheimer's disease.
- To correlate microglial activation markers with specific disease stages, including pre-plaque, onset, and significant plaque load.
Main Methods:
- Utilized Iba1 immunohistochemistry to assess microglial morphology in the primary motor cortex and somatosensory barrel fields of APP/PS1 mice and age-matched controls.
- Performed immunohistochemistry for pro-inflammatory markers (CD14, CD40) and anti-inflammatory markers (CD16, TREM2) at 3, 6, and 12 months of age.
Main Results:
- Observed a significant increase in deramified microglial morphologies in APP/PS1 mice at 6 and 12 months, with a decrease in ramified microglia at 12 months.
- Demonstrated heterogeneous marker immunoreactivity, with CD16, TREM2, and CD40 associated with activated morphology.
- Found significant upregulation of all inflammatory markers (TREM2, CD40, CD14, CD16) at 12 months in APP/PS1 mice compared to controls.
Conclusions:
- Microglial response in the APP/PS1 Alzheimer's disease model is complex, exhibiting both pro- and anti-inflammatory marker expression.
- Morphological changes in microglia are evident and correlate with disease progression and inflammatory marker upregulation.
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