Putting Human Microglia into Alzheimer’s Mice

University of California, Irvine, researchers have made it possible to learn how key human brain cells respond to Alzheimer’s. By developing a way for human microglia to grow and function in mice, the scientists were able to study the mechanisms contributing to the disease at a new angle. The team claims that their breakthrough also holds promise for investigating many other neurological conditions such as Parkinson’s, traumatic brain injury, and stroke. The study was published yesterday in Neuron.

To create the specialized mouse, the team generated induced pluripotent stem cells (iPSCs) using cells donated by adult patients. The researchers then coaxed the iPSCs into becoming young microglia and implanted them into genetically modified mice. Examining the rodents several months later, the scientists found that about 80% of the microglia cells in their brains were human.

“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s,” says senior author Mathew Blurton-Jones. “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.”

In verifying the chimeric model’s effectiveness for these investigations, the team checked how its human microglia reacted to amyloid plaques—protein fragments in the brain that accumulate in people with Alzheimer's. Indeed, the human microglia imitated the expected response by migrating toward the amyloid plaques and surrounding them.

“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.

Understanding the stages of the disease, which, according to the Alzheimer’s Association, can last from two to twenty years, has been among the challenges facing researchers.  “This specialized mouse will allow researchers to better mimic the human condition during different phases of Alzheimer’s while performing properly-controlled experiments,” says first author Jonathan Hasselmann.