Chimeric "mighty mouse" with human brain cells to advance Alzheimer’s research
Researchers from University of California, Irvine have developed a new transgenic mouse model with human brain immune cells. The novel breakthrough will allow scientists the ability to observe how human brain cells respond to different Alzheimer's-inducing toxic proteins, significantly advancing our understanding into how neurodegenerative disease progresses.
One of the big hurdles facing Alzheimer's and dementia researchers is the lack of an effective animal model for testing new treatments. Hundreds of human clinical trials investigating potential treatments have failed in recent years, despite promising results in early animal testing phases. It has become increasingly clear that our standard animal models for this disease are insufficient, and it's not entirely surprising. After all, apart from some rare recent discoveries, Alzheimer's disease isn't known to clearly appear in any animal other than humans.
MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) is an ongoing collaborative project launched in 2016 to tackle this major research problem. The program's goal is to produce at least 40 prospective mouse models for scientists to use to further Alzheimer's research.
Separate to MODEL-AD's work, a team from UC Irvine has just produced an entirely new transgenic mouse model, for the first time producing an animal containing functional and growing human microglia, a vital immune cell present in human brains. Some researchers hypothesize dysfunctional microglia play a major role in the neurodegeneration associated with Alzheimer's.
"Microglia are now seen as having a crucial role in the development and progression of Alzheimer's," explains Mathew Blurton-Jones, team leader on the research. "The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer's and the majority of these are switched on in microglia. However, so far we've only been able to study human microglia at the end stage of Alzheimer's in post-mortem tissues or in Petri dishes."
The mice were created by implanting microglia, generated from human induced pluripotent stem cells, into genetically modified mice. After a few months the researchers saw the human microglia had spread to comprise around 80 percent of all microglia in the animals' brains. When toxic proteins known to aggregate in human Alzheimer's brains were introduced into the animals, the microglia responded in a unique way similar to that of human microglia.
"The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cells," says Blurton-Jones.
Blurton-Jones refers to the research as the "mighty mouse" breakthrough and suggests it will have applications beyond just studying Alzheimer's. Understanding the effects of human immune cells in the brain could assist researchers looking at everything from Parkinson's and other neurological disorders, to traumatic brain injury and stroke.
The new research was published in the journal Neuron.
Source: UCI News