Chimeric model means improvement for Alzheimer's research

Studying the development of Alzheimer’s disease presents unique challenges, as brain cells behave differently in vivo and in vitro. Using mice as models presents useful insights but mouse models never fully develop the disease despite the fact that their brains and brain cells are quite similar to their human counterparts.

Researchers have now transplanted human brain cells into mouse brains that mimick some of the hallmarks of Alzheimer’s disease, including the presence of amyloid plaques. They found that, compared to mouse brain cells, human brain cells are much more sensitive to amyloid plaque pathology. This novel model allows for a better characterization of the disease processes that actually take place in the brain of human patients.

Much of the work was performed in close cooperation with Professor Pierre Vanderhaeghen (ULB-WELBIO, VIB-KU Leuven), whose lab previously pioneered the technology to differentiate human pluripotent stem cells into brain cells in vitro, and then transplant them in the mouse brain, generating a human/mouse chimera.

This new chimeric model allows for a better characterization of the disease processes that actually take place in the brain of human patients. “We relied heavily on the insights and expertise of Pierre Vanderhaeghen and his lab to set up this new AD model," says Professor Bart De Strooper.

"With this novel experimental technique, we can study how different cell types in the human brain respond to the Alzheimer's pathology and hopefully unravel the link between amyloid and tau protein pathology – which leads to neuron death and is the holy grail of current Alzheimer’s research.”

“While many features of the brain are conserved between different species such as humans and mice," Professor Vanderhaeghen continues, " the human brain displays a number of characteristics, which make us what we are, as a species and as individuals. However, studying this human-specific part remains a big challenge in neuroscience. This study is exciting because it constitutes a first proof of principle that stem cell-based models of transplanted human neurons can be applied to study an important neurological disease.”

Moving forward, Professor De Strooper and his team are already planning a screen to identify human genes that protect against cell death associated with Alzheimer’s disease. De Strooper: “Now that we are able to investigate the disease by observing human cells directly, we can make progress in this field of research at a considerably faster pace. The eventual end goal of the screening is to identify new drug targets within human cells themselves, something that was never possible before.”