Zebrafish is not far from humans when it comes to how the brain is affected by Alzheimer’s disease

Our recent publication about comprehensive comparison of the single cell/nucleus transcriptomics profiles of human Alzheimer’s brains and zebrafish Alzheimer’s model is out. We found remarkable similarities and biologically meaningful differences.

To compare transcriptomics data in zebrafish model of AD and Alzheimer’s patients (in entorhinal cortex, superior frontal gyrus, dorsolateral prefrontal cortex), we first reliably integrated the zebrafish-human datasets together. 95% of the cells could be directly co-clustered. We identified major cell types including neurons, astroglia, immune cells, oligodendrocytes and endothelial cells. Their signature molecular pathways in humans and zebrafish were similar, which confirmed our integration strategy.

When we compared the gene expression changes in Alzheimer’s vs controls in #zebrafish and humans, we found remarkable similarity in neurons. Zebrafish neurons are affected by amyloid toxicity similar to human #neurons. Interesting difference was in astroglia, which have many functions including neurogenesis. Neurogenesis-related pathways are enriched in zebrafish, supporting once again the pathology-induced neurogenic capacity seen in zebrafish might be lost in humans.

Concordant gene expression changes in human and zebrafish astroglia in Alzheimer’s were related to protein clearance and removing toxic proteins; while non-synergistic changes were related to neurogenesis, RNA processing and transcription factor activity. This showed that the neurogenic output in Alzheimer’s disease could be a determining factor on how well we cope with the disease. The more neurogenesis the better resilience!

Zebrafish is an amazing model to learn how our brains could be made more neurogenic in Alzheimer’s. By comparing single cell sequencing data from human fetal brains, we also found that zebrafish brain – with its neurogenic activity, is more close to developing human brain where #neurogenic activity is pronounced. Zebrafish can also tell us how we could rejuvenate our brains!

When we compared the microglia – the brain’s #immune cells – in the #human and zebrafish brains, we found similar inflammatory profiles upon disease. Zebrafish will serve as a useful animal model for investigating the human microglial response in Alzheimer’s.

Zebrafish is becoming a stronghold of neurogenesis-related work and we are happy to see that it is providing us unprecedented knowledge to illuminate pathological mechanisms of human diseases, such as Alzheimer’s. Maybe in the future it’ll also help to intervene and cure!

In combination with recent previous work that brings together clinical studies in human and zebrafish, we are confident that there is a promising route ahead in utilizing zebrafish for Alzheimer’s disease.

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