Amyloid-β & the Inflammatory Microenvironment in an APP/PS1 Mouse Model of Alzheimer's Disease

Last Updated Date: August 20, 2024

Authors: Robin Guay-Lord, Laurent Potvin-Trottier, Ph.D., Lionel Breuiland, Ph.D., Elodie Brison, Ph.D., Jim Paskavitz, M.D., Barry J. Bedell, M.D., Ph.D.

Key Takeaways

• Activated microglia and reactive astrocytes are often in close spatial proximity to β-amyloid plaques.
• Using automated image analysis methods, the "inflammatory microenvironment" of plaques can be defined on multiplex immunofluorescence tissue sections.
• In an APP/PS1 transgenic mouse model of Alzheimer's disease, we have evaluated the neuroinflammatory state in the vicinity of amyloid pathology as a function of age.
• We have found a complex spatial relationship between resting and activated neuroinflammatory cells and Aβ plaques.
• Our novel approach may provide sensitive measures for the preclinical evaluation of putative disease-modifying therapeutics in animal models of Alzheimer's disease.

Neuroinflammation is a key feature of Alzheimer's disease (AD). The "inflammatory microenvironment" of amyloid-β pathology is gaining significant attention as a target for therapeutic intervention.

Microglia and astrocytes undergo phenotypic changes as part of AD pathogenesis.  Improving our understanding the spatial relationships between β-amyloid and the various phenotypes of microglia and astrocytes is expected to provide new avenues for disease modification.  

We have combined advanced image analysis methods with high-resolution multiplex immunofluorescence (IF) data to explore the changes in microglia and astrocytes in the neighborhood of β-amyloid plaques. We have applied this novel spatial biology framework to brain tissue sections from a transgenic mouse model of AD that demonstrates progressive pathology with a well-defined spatiotemporal pattern.

Analysis of the Aβ plaque microenvironment showed microgliosis primarily localized less than 10 µm away from the plaques, with higher Iba-1 stain density, total microglia density, and activated microglia density compared to wild-type (WT) mice. Interestingly, the astrogliosis also showed an increase with proximity to the plaques, but was also increased outside of the local plaque microenvironment. Of particular relevance was the observation of high levels of activated microglia in intimate contact (0 µm distance) with the plaques. 

By restricting the analysis to quantify inflammation in the core of the plaques and comparing it to neuroinflammation levels outside of the plaques, we found a significant difference between the global levels in WT mice and the plaque core levels as early as 6 months-of-age in transgenic mice for both activated microglia density and GFAP stain density. This significant difference was not observable when solely comparing global levels for the same metric at 6 months. Interestingly, the core levels of GFAP and activated microglia density did not appear to change with increasing age. Conversely, we observed a time-dependent increase in the neuroinflammation outside of the plaque, suggesting that the majority of the observable microgliosis and astrogliosis in early pathology is located in close proximity to plaques and tends to increase further away from the plaques as the pathology progresses.

We anticipate this novel, spatial biology approach will prove useful for the preclinical assessment of experimental therapeutic agents of experimental, disease-modifying therapeutic agents for Alzheimer's disease. 

Presentation Highlights