Alzheimer’s disease is a type of dementia that is characterised by the build-up of plaque in the brain. This build-up can occur for decades before the disease is diagnosed, and it ultimately leads to loss of brain tissue and death. Frances Edwards, Professor of Neurodegeneration at University College London, used a range of mouse models to examine plaque load in mice at 9 months, 24 months, and 30 months. The principal goal was to use genetically engineered knock-in mice (NLF) to accurately model Alzheimer’s disease in humans.
The NLF mouse had less plaque at 24 months than the more commonly used NLGF mouse model had at four months. This initial result implies that gene expression changes and what occurs at a pathological level varies depending on age. The NLF mouse model is preferred for its slow plaque development, which better mimics human sporadic Alzheimer's disease compared to other mouse models including transgenic ones.
RNA sequencing helped to identify differentially expressed genes linked to plaques and disease progression. Meanwhile spatial transcriptomics came in handy when analysing gene expression changes in microglia when they were near or in contact with plaques, which are not detectable in whole tissue RNA sequencing. This shows how these techniques complement one another to give Edwards an idea of the bigger picture.
Trem2 is a microglial gene associated with Alzheimer’s risk. The whole brain RNAseq only showed minor changes but spatial transcriptomics showed major upregulation near plaques. A deeper look into Trem2’s purpose showed that a Trem2 gene mutation (R47H variant) reduced many plaque-induced gene changes, positing that TREM2 is essential for microglial activation near plaques.
Edwards took the research a step further by exploring how microglia behaviour changes depending on their proximity to plaques. Those on plaques exhibited strong gene activation, whereas those near plaques showed moderate activation, and those far from plaques had gene expression levels closer to baseline. Moreover, astrocytes, another brain cell type, also displayed unique gene expression patterns in response to plaque presence.
The key and arguably most complicated challenge involved translating these findings to human Alzheimer’s disease. Therefore, the scientists examined human brain tissue from 28 Alzheimer’s patients, including individuals with TREM2 and APOE gene variants. Unfortunately, they encountered significant RNA degradation issues, which complicated spatial transcriptomic studies. Edwards explained that they experimented with RNAscope and fluorescence lifetime imaging microscopy (FLIM) to improve RNA detection, with ongoing tweaks.
All in all, spatial transcriptomics provides unmatched insights into microglial and astrocyte interactions with plaques, highlighting TREM2’s essential role in the disease process. Future research will focus on enhancing RNA quality in human brain samples, expanding spatial transcriptomic studies to human Alzheimer’s Disease brains.
