Our bodies use a protective barrier to shield the brain from harmful substances in the blood while still allowing essentials like glucose and oxygen to enter. As in other tissues, brain blood vessels are lined with endothelial cells. In the brain, these cells form extremely tight junctions, making it nearly impossible for most substances to pass through the vessel wall and into brain fluid.

Blood-brain barrier

Recent studies show that defects in the blood‑brain barrier occur in neurodegenerative disorders like Huntington’s disease and make the barrier leakier. Although Huntington’s symptoms—such as involuntary movements, mood swings, and trouble swallowing—stem mainly from the loss of specific nerve cells, barrier breakdown likely contributes to brain deterioration.

What remains unclear is whether Huntingtin mutations directly damage the endothelial cells that form the blood‑brain barrier or whether these cells are harmed indirectly as the disease progresses. This distinction matters. If Huntingtin mutations directly affect the barrier, it could broaden our understanding of how this fatal disease works and open new therapeutic avenues.

UC Irvine team

A UC Irvine team answered this question using induced pluripotent stem cells from people with Huntington’s disease. Their CIRM‑funded study appeared in Cell Reports.

For the first time in a neurodegenerative disease, the team coaxed Huntington’s iPSCs into brain microvascular endothelial cells, the cells that form the blood‑brain barrier. The Huntington’s BMECs were dysfunctional. Compared to healthy BMECs, they formed fewer vessels, and the vessels they made were leakier. This shows the Huntingtin mutation directly harms the blood‑brain barrier.

The team then compared gene activity in healthy and Huntington’s BMECs. They found that Wnt genes were overactive in Huntington’s BMECs. This overactivity explained the leaks. A Wnt inhibitor fixed the defects. Dr. Leslie Thompson summarized the impact in a press release.

“Now we know there are internal problems with blood vessels in the brain. This discovery may guide future treatments to seal leaky vessels and improve drug delivery for HD patients.”

iPSCs

A companion Cell Stem Cell report used the same iPSC‑derived blood‑brain barrier model. In that study, Cedars‑Sinai researchers identified BMEC defects as the cause of Allan‑Herndon‑Dudley syndrome, a neurological disorder that leads to cognitive and movement problems. Together, these findings highlight the importance of studying blood‑brain barrier function in neurodegenerative disease.

Dr. Ryan Lim, first author of the UC Irvine study, emphasized the broader significance.

“These studies show the power of iPSCs to help us understand human disease.”