December 13, 2024
Yamaguchi University
Keio University
Key Points of the Announcement
Using iPS cell technology, we generated brain microvascular endothelial-like cells derived from familial ALS patients (with TARDBP mutations) and examined their barrier function in detail.
We demonstrated for the first time in a human model that the genetic background of familial ALS patients leads to abnormalities in the blood-brain barrier (BBB), suggesting the potential involvement of BBB breakdown in the progression of ALS.
As a new finding regarding the pathology of ALS, we proved that this barrier dysfunction in brain endothelial cells occurs independently of inflammation or neuronal damage.
We identified that the barrier dysfunction is caused by a decrease in Wnt/β-catenin signaling, which is crucial for BBB development and maintenance, and confirmed that activating this signaling pathway repairs the barrier.
Amyotrophic lateral sclerosis (ALS) is an intractable disease in which motor neurons progressively degenerate, and there is still no effective treatment. Recent studies using animal models have revealed that abnormalities in the blood-brain barrier (BBB), a protective barrier for the brain, are involved in its progression. Now, a research team led by Assistant Professor Hideaki Nishihara of the Graduate School of Medical Sciences at Yamaguchi University, in a joint study with research groups from Keio University and the Tohoku University Graduate School of Medicine, has established a new human BBB experimental model using iPS cells derived from familial ALS patients, revealing that this barrier function may be affected by the genetic background of these patients.
In this study, brain microvascular endothelial cells (BMECs), which constitute the BBB, were generated from familial ALS patients. A detailed investigation of their barrier function confirmed that patient-derived cells have abnormal barrier function, increasing the risk of harmful substances entering the brain. Furthermore, this barrier dysfunction in brain endothelial cells occurs independently of inflammation or neuronal damage, providing new insights into the pathology of ALS.
The research team also demonstrated that activating Wnt/β-catenin signaling can repair the abnormalities in patient-derived BMEC-like cells, thereby improving barrier function. This indicates that the model is also useful for screening therapeutic drugs for barrier dysfunction in ALS patients, and it is anticipated that this will advance the development of new treatment methods.
This research is a significant achievement in that it elucidates the role of BMECs in ALS and presents a new approach toward treatment. The results of this study were published in the journal *Frontiers in Cell and Developmental Biology* on August 15, 2024.
For the full press release, please see below.