Scientists at the University of California, Irvine, report that they used a chimeric model to learn how key human brain immune cells respond to Alzheimer’s. By developing a way for these microglia to grow and function in mice, the team says researchers now have an unprecedented view of crucial mechanisms contributing to the disease.

The scientists, led by Mathew Blurton-Jones, PhD, associate professor of neurobiology & behavior, believe their findings also hold promise for investigating many other neurological conditions such as Parkinson’s, traumatic brain injury, and stroke. Their study (“Development of a Chimeric Model to Study and Manipulate Human Microglia in vivo”) appears in Neuron.

Chimeric Model Alzheimer's graphical abstract
Source: Cell

“PSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition,” write the investigators.

“To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We, therefore, have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.”

To create the specialized mouse, the team generated induced pluripotent stem cells, iPSCs0, using cells donated by adult patients. Once created, iPSCs can be turned into any other type of cell. In this case, the researchers coaxed the iPSCs into becoming young microglia and implanted them into genetically-modified mice. Examining the rodents several months later, the scientists found about 80% of the microglia in their brains was human, opening the door for an array of new research.

“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s,” said 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 the amyloid plaques in the brain that accumulate in people with Alzheimer’s. They 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,” Blurton-Jones said.

“This specialized mouse will allow researchers to better mimic the human condition during different phases of Alzheimer’s while performing properly-controlled experiments,” noted Jonathan Hasselmann, one of the two neurobiology & behavior graduate students involved in the study. Understanding the stages of the disease, which according to the Alzheimer’s Association can last from two to 20 years, has been among the challenges facing researchers.

Neurobiology and behavior graduate student and study co-author Morgan Coburn said: “In addition to yielding vital information about Alzheimer’s, this new chimeric rodent model can show us the role of these important immune cells in brain development and a wide range of neurological disorders.”

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