This article was compiled from a recent webinar, delivered by Professor Bart de Strooper, who is the Director of UK Dementia Research Institute, UCL. You can watch the webinar ‘Integrative Single Cell and Spatial Analysis’ on demand here.
Professor Bart de Strooper is a world-renowned Alzheimer’s disease (AD) researcher. Recently, he has worked on a cellular theory for Alzheimer’s to explain how different cell types trigger the progressive disease process.
Alzheimer’s disease (AD) is a particular form of dementia that is associated with neurodegeneration. Genetics plays a huge role in AD. Extensive research has been conducted into the different genes that contribute to its progression and, also, into the few genes which protect against the disease.
In a brain affected with AD, beta-amyloid proteins gather in abnormal numbers and clump together to form plaques that collect between the neurons and disrupt cell function. Although complex alterations have been observed around the amyloid plaques of AD, little is known about the molecular changes and interactions that characterise this response.
Analysing Alzheimer’s disease
Prof. De Strooper and his team utilised spatial transcriptomics to study the genes that invoke Alzheimer’s disease. Risk genes were found to be expressed in numerous different cell types, mostly in the microglia, but also in astroglia and in the vasculature. The molecular profiling method allowed the scientists to measure all the gene activity in a brain tissue sample and map how the different genes in varying cell types changed over the course of the disease.
Using spatial transcriptomics, the team examined AD mouse models to investigate the transcriptional changes that occurred in a 100-μm diameter around amyloid plaques.
The main findings were as follows:
- Early alterations in a gene co-expression network, enriched for myeline and oligodendrocyte genes (OLIGs), was observed.
- A multicellular gene co-expression network of plaque-induced genes (PIGs) was prominent in the later phase of the disease. This involved the complement system, oxidative stress, and lysosomes.
Essentially, amyloid plaques were found to trigger a series of cellular reactions, creating much activity in the surrounding area of the plaques. These reactions may, or may not, lead to dementia. Further documentation of these cellular responses is crucial so that the consequences of these triggered reactions can be understood. Microglia were also found to be central players in the transduction of amyloid toxicity and it was clear that microglia work together with astroglia in response to plaque formation, as coordination of their genes was discovered.
The future of spatial transcriptomics and Alzheimer’s disease
These findings provide the possibility of predicting the best treatment for AD, depending on the phase of the disease. For example, in the early stages it may be useful to remove amyloid plaques as this could abort several of the following phases. On the other hand, once the cellular responses are present, it may be more effective to attack the microglia and astroglia.
Genome-wide spatial transcriptomic analysis provided an unprecedented approach to explore the cellular network within the vicinity of pathogenic amyloid plaques in AD brains. This technology has the potential to untangle the mechanisms behind the progression of AD and it is highly conceivable that spatial transcriptomic techniques can be transferred to other neurodegenerative diseases, ultimately improving patient outcomes in the future.
“There are huge strengths of these new spatial transcriptomic approaches for the study of a complex disorder like Alzheimer’s disease. Particularly in the brain, it’s extremely important to use these approaches because they allow you to keep the cellular and spatial information. This is especially important in the brain with all of its many different cell types, and where spatial specialisation is extremely important.”
If you are interested in the application of single cell and spatial technologies in Neuroscience, you can catch our upcoming ‘Reimagine Neuroscience with Single Cell and Spatial Multiomics’ webinar by registering here.
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