A recent study from the Gladstone Institutes and UC San Francisco (UCSF) has unveiled that blood vessels and immune cells, long recognized for their protective functions in the brain, may also be pivotal in the risk of developing neurological diseases such as Alzheimer’s and stroke. This groundbreaking research highlights the role of these guardian cells in how genetic risk factors influence brain health.
For many years, the focus of neurological research has primarily centered on neurons. According to Andrew C. Yang, Ph.D., a Gladstone Investigator and senior author of the study, “When studying diseases affecting the brain, most research has focused on its resident neurons.” He expressed hope that the findings will shift the focus to the cells that form the brain’s protective barriers, suggesting they may play a crucial role in diseases like Alzheimer’s.
The research, published in the journal Neuron, addresses a longstanding mystery regarding the origin of genetic risks associated with neurological disorders. It suggests that vulnerabilities in the brain’s defense system may trigger these diseases, shifting the paradigm of how scientists approach brain health.
Mapping Genetic Risks in Brain Cells
Large-scale genetic studies have previously identified numerous DNA variants linked to increased risks of conditions such as Alzheimer’s, Parkinson’s, and multiple sclerosis. Notably, over 90% of these variants reside not within the genes themselves, but in surrounding non-coding DNA, often dismissed as “junk DNA.” These regions function as complex switches that regulate gene expression.
To better understand these mechanisms, the researchers developed a novel technology named MultiVINE-seq, which isolates vascular and immune cells from postmortem human brain tissue. This allowed them to simultaneously map gene activity and chromatin accessibility within each cell type, providing unprecedented insights into how genetic risk variants operate across major brain cell types.
Examining 30 brain samples from individuals with and without neurological diseases, the team, including lead authors Madigan Reid, Ph.D., and Shreya Menon, integrated findings with extensive genetic data related to Alzheimer’s and stroke. The results revealed that many disease-associated variants were active in vascular and immune cells rather than neurons.
Reid noted, “Before this, we knew these genetic variants increased disease risk, but we didn’t know where or how they acted in the context of brain barrier cell types.”
Diverse Mechanisms in Disease Risk
One of the most significant revelations from the study is that genetic risk variants disrupt the brain’s barrier system differently depending on the disease. The researchers found that the genetic drivers for stroke and Alzheimer’s have distinct effects, even though both conditions involve the brain’s blood vessels.
Reid remarked on the findings, stating, “We were surprised to see that the genetic drivers for stroke and Alzheimer’s had such distinct effects.” In the case of stroke, the genetic variants primarily impacted genes associated with the structural integrity of blood vessels, indicating a potential weakening of the vessels’ physical structure. Conversely, in Alzheimer’s, the variants amplified genes that control immune activity, suggesting that overactive inflammation is a critical issue rather than structural weakness.
Among the variants associated with Alzheimer’s, one particular variant near the PTK2B gene was notably active in T cells, a type of immune cell. This variant enhances the expression of PTK2B, which may lead to increased T cell activation and entry into the brain, exacerbating immune responses. The research found these hyperactive immune cells positioned near amyloid plaques, the protein aggregates characteristic of Alzheimer’s.
Yang emphasized the significance of this finding, stating, “Here, we provide genetic evidence in humans that a common Alzheimer’s risk factor may work through T cells.” Importantly, PTK2B is recognized as a “druggable” target, with therapies designed to inhibit its function currently undergoing clinical trials for cancer. This opens a potential pathway for repurposing these drugs for Alzheimer’s treatment.
The study’s findings emphasize the critical location of the brain’s vascular and immune cells at the intersection of the brain and body. These cells are continually influenced by lifestyle and environmental factors, which may interact with genetic predispositions to drive disease. Their unique positioning highlights them as promising targets for future therapeutic interventions that could strengthen the brain’s defenses without needing to penetrate the blood-brain barrier.
Yang concluded, “Our work could inform new, more accessible drug targets and lifestyle interventions to protect the brain from the outside in.” The implications of this research are profound, potentially paving the way for innovative approaches to mitigate the risks associated with neurological diseases.
