Highly regenerative species such as zebrafish can regrow limbs and organs, and are also capable of far greater regrowth in response to damage in the brain than is the case in mammals. Researchers here explore the mechanisms involved in the zebrafish response to an Alzheimer's-like environment and neural cell death. As is the case for many research projects involving zebrafish, the goal is to pin down enough of the biochemistry of exceptional regeneration to understand how it differs from humans, and thus how this capability might be recreated in our species.
Zebrafish have an extensive ability to replenish the lost neurons after various types of damage, and the researchers have shown that it can also do so after Alzheimer-like neurodegeneration. This is an ability humans do not have. Evolutionarily, the zebrafish and human beings are very similar: the cell types in the zebrafish brain and their physiological roles are very similar to humans, and more than 80 percent of the genes humans have are identical in the zebrafish. Therefore, zebrafish are an ideal model for studying complex diseases of humans in a very simplistic way. "We believe that understanding how zebrafish can cope with neurodegeneration would help us to design clinical therapy options for humans, such as for Alzheimer's disease. Within this study, we observed Alzheimer-like conditions in the fish brain. We found that zebrafish can impressively increase the neural stem cell proliferation and formation of new neurons even after Alzheimer's-like pathology. This is amazing because to treat Alzheimer's we need to generate more neurons. And this all starts with neural stem cell proliferation, which fails in our diseased brains."
This study has shown that Alzheimer's disease symptoms can be recapitulated in the zebrafish brain using a short section of human APP protein that is a hallmark of Alzheimer's disease (Amyloid-β42). This protein part causes the death of neurons, inflammation, loss of neuronal connections and deficits in memory formation in zebrafish. The researchers found that the immune-related molecule Interleukin-4 (which is also present in the human brain) is produced by the immune cells and dying neurons in the fish brain. This molecule alerts the neural stem cells that there is danger around. Stem cells then start to proliferate through a cell-intrinsic mechanism involving another protein of central function called STAT6. The importance of this study lies in the notion that the diseased brain and the inflammatory milieu there can be modulated to kick-start neural stem cell proliferation, and this is exactly what successfully regenerating vertebrates do. The next steps towards an understanding of Alzheimer's disease are clearly defined: "We will go on identifying more factors required for a successful 'regeneration' response in fish brain after an Alzheimer's disease-like situation. By doing so, we can get a more complete picture of the molecular programs beneficial for tackling this atrocious disease. Zebrafish will tell us the candidate genes we should focus on in our brains for possible regenerative therapies."