A groundbreaking study reveals molecular triggers behind cerebral small vessel disease, along with a promising drug that could restore vital vascular functions.
Researchers at LMU University Hospital have made significant strides in understanding the origins of cerebral small vessel disease—a condition that poses serious risks including reduced blood flow, bleeding, and significant strokes. This illness is also recognized as a major contributor to dementia. The findings from this pivotal research have been published in the esteemed journal, Nature Neuroscience.
Given the alarming prevalence of this grave condition—strokes being the leading cause of long-term disability and the second most common cause of death—it is astonishing, as noted by Professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research (ISD) at LMU University Hospital Munich and an incoming spokesperson for the SyNergy Cluster of Excellence, that "medicine has known comparatively little about the cellular and molecular mechanisms that lead to cerebral small vessel disease." One challenge lies in the difficulty of directly examining the minuscule vessels within the human brain. Additionally, there has been a scarcity of appropriate experimental models that allow researchers to thoroughly investigate the cellular or molecular dynamics of small vessel disease, whether in laboratory settings or in living organisms.
In recent years, however, the research team in Munich has successfully genetically modified mice to specifically disable the ability of their endothelial cells to produce certain proteins. Endothelial cells are crucial because they line the blood vessels, serving as a barrier through which blood flows, and are often where this disease begins. By selectively deactivating the Foxf2 gene—previously identified by the researchers as a gene associated with stroke risk—these endothelial cells produced no corresponding protein, resulting in dysfunction of the small cerebral vessels, particularly affecting the blood-brain barrier that safeguards the brain from harmful substances. Professor Dichgans elaborates, stating, "This indicates that the lack of Foxf2 is undoubtedly one of the key factors contributing to cerebral small vessel disease."
Foxf2 acts as a transcription factor, meaning it helps activate various other genes. The researchers discovered that among these is the Tie2 gene and its associated components within the Tie signaling pathway. The activation of Tie2 and the proper functioning of this pathway are vital for maintaining healthy blood vessels. In the absence of Tie2, there is an increased risk of inflammatory responses within the endothelial cells of larger blood vessels, which can lead to atherosclerosis and elevate the risks of stroke and dementia. Dichgans adds, "We validated our findings across multiple molecular levels, and they were corroborated through experiments involving human cells conducted in collaboration with Professor Dominik Paquet, another senior author of the study."
Furthermore, the researchers experimented with a therapeutic approach that targets the compromised function of small cerebral vessels informed by their new discoveries. They tested a drug candidate known as AKB-9778, which specifically activates the Tie2 pathway. According to the LMU neurologist, "Thanks to this treatment, we were able not only to normalize the Tie2 signaling pathway but also to restore the impaired function of the blood vessels. This therapy holds the potential to reduce the risks for both stroke and dementia."
"I would be thrilled to share that we are working on preparing a clinical study to evaluate this compound in patients," Dichgans expresses. "However, accessing the substance at present is challenging, as it is currently undergoing clinical evaluations for other conditions." The research team is actively pursuing related compounds that may be suitable for clinical trials focused on small vessel disease.
In summary, this study sheds light on crucial molecular mechanisms of cerebral small vessel disease and opens the door for potential therapeutic interventions that could alter the course of this debilitating condition.
