By using induced pluripotent stem cells to create endothelial cells that line blood vessels in the brain for the first time for a neurodegenerative disease, researchers have learned why Huntington’s disease patients have defects in the blood-brain barrier that contribute to the symptoms of this fatal disorder. The study, which is the first induced pluripotent stem cell-based model of the blood-brain barrier for a neurodegenerative disease, was published in Cell Reports.

The blood-brain barrier protects the brain from harmful molecules and proteins. It has been established that in Huntington’s and other neurodegenerative diseases there are defects in this barrier adding to HD symptoms. What was not known was whether these defects come from the cells that constitute the barrier or are secondary effects from other brain cells.

To answer that question, researchers reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into brain microvascular endothelial cells — those that form the internal lining of blood vessels and prevent leakage of blood proteins and immune cells.

The researchers discovered that blood vessels in the brains of HD patients become abnormal due to the presence of the mutated Huntingtin protein, the hallmark molecule linked to the disease. As a result, these blood vessels have a diminished capacity to form new blood vessels and are leaky compared to those derived from control patients.

The chronic production of the mutant Huntingtin protein in the blood vessel cells causes other genes within the cells to be abnormally expressed, which in turn disrupts their normal functions, such as creating new vessels, maintaining an appropriate barrier to outside molecules, and eliminating harmful substances that may enter the brain.

In addition, by conducting in-depth analyses of the altered gene expression patterns in these cells, the researchers identified a key signaling pathway known as the Wnt that helps explain why these defects occur. In the healthy brain, this pathway plays an important role in forming and preserving the blood-brain barrier. The researchers showed that most of the defects in HD patients’ blood vessels can be prevented when the vessels are exposed to a compound (XAV939) that inhibits the activity of the Wnt pathway.

Paper: “Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits”
Reprinted from materials provided by the University of California, Irvine.