Using Spatial Transcriptomics to Investigate Alzheimer's Disease
Summary
In this study, researchers used spatial transcriptomics to investigate molecular alterations and cellular interactions in tissues around amyloid plaques in an Alzheimer's disease (AD) animal model. They found changes in a gene co-expression network enriched for myelin and oligodendrocyte genes early in the disease, as well as a multicellular gene co-expression network called "plaque-induced genes" (PIGs) that emerged later and involved the complement system, oxidative stress, lysosomes, and inflammation. These changes were confirmed using in situ sequencing on the mouse and human brain slices. This research offers a new method for understanding disturbed cellular networks in the pathogenic hallmarks of AD and other brain illnesses.
Fig.1 Graphical Abstract. (Chen, 2020)
Research Criteria
Using spatial gene expression they evaluate the genome-wide transcriptome modifications caused by amyloid plaques in hundreds of small tissue domains (TDs) (ST). In addition to this procedure, they utilized an alternative in situ sequencing method that allowed them to observe hundreds of selected transcripts in cellular detail. In addition, they compiled the information into a database (https://www.alzmap.org/).
Fig.2 Experimental design. (Chen, 2020)
Sample Type
Tissue sections from mouse and human brains.
Result—ST in Adult Mouse Brains
After collecting three adjacent coronal slices, the middle one was processed for spatial transcriptomics while the other two sections were immunostained. The slices were arranged in a triangular pattern (ST). Using t-distributed stochastic neighbor embedding, 10,327 transcriptome profiles were categorized according to their location inside the brain (t-SNE). The capacity of ST to precisely identify different parts of the brain was demonstrated by the fact that the profiles and landmark genes covering the somatic layers of the hippocampus considerably differentiated between the CA1, CA3, and DG subregions. Although the sites for wild-type mice overlap at 12 and 18 months of age, the AppNL-G-F transcriptomics profile is different between these two time points, which suggests that the disease progresses during this period.
Fig.3 Spatially resolved transcriptomics profiles in adult mouse brain. (Chen, 2020)
Result—Linking Gene Expression Alterations to Aβ Accumulation
Amyloid deposition begins in AppNL-G-F mice at 3 months of life, and at 18 months, 1,565 ± 167 plaques with surfaces measuring between 78.5 and 4.950 μm2 are found in each section. The researchers separated mild from extreme Aβ accumulation using the standard deviation of Aβ fluorescence intensity as an "Aβ index," and discovered that Aβ proceeds from the dorsal to the ventral cortex, thalamus, and hippocampus, consistent with Aβ immunostaining.
Fig.4 Linking gene expression alterations to Aβ load. (Chen, 2020)
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Reference
- Chen, W.; et al. Spatial transcriptomics and in situ sequencing to study Alzheimer's disease. Cell. 2020, 182(4): 976-991.
