A recent study published in the journal Brain reveals that damage to small blood vessels associated with the hereditary condition CADASIL may significantly impact brain functions, particularly in the hippocampus, which is crucial for memory. This research sheds light on the cognitive issues and dementia that frequently affect individuals with CADASIL, a condition caused by genetic mutations in the NOTCH3 gene that lead to the degeneration of vascular smooth muscle cells and reduced cerebral blood flow.
Understanding the molecular effects of CADASIL on brain cells has been challenging, as the disease is primarily recognized for causing strokes and alterations in white matter. Researchers at Karolinska Institutet in Sweden undertook a comprehensive investigation, employing a variety of approaches including a humanized mouse model that carries a CADASIL-related gene variant, post-mortem human brain tissue, and human vascular smooth muscle cells.
Key Findings on Neuronal Activity and Blood Vessel Health
The study’s findings indicated that the mouse model with CADASIL exhibited impaired gamma oscillations in the hippocampus, brain rhythms essential for memory and learning. The researchers observed that these mice had shorter neuronal fibers and abnormal neuron shapes, patterns that were also evident in human brain tissue from CADASIL patients.
“We saw clear changes in both neuronal structure and function,” stated Wenchao Shao, a PhD student at the Department of Neurobiology, Care Sciences and Society. “These findings point to a vulnerability in the hippocampus that has not been fully recognized before.”
Moreover, the researchers noted a significant reduction in the levels of mitochondrial respiratory complexes within the hippocampus of the mice, as well as in human vascular cells. This decline was associated with diminished oxygen consumption and ATP production, alongside a decrease in glycolytic capacity. Concurrently, these cells exhibited heightened expression of pro-inflammatory genes.
In the mouse model, the research team found that the hippocampal blood vessels accumulated the NOTCH3 extracellular domain, leading to a loss of vascular smooth muscle cells and a decrease in vessel density. Imaging studies revealed increased attachment of microglial cells to these vessels, identifying a specialized subgroup of microglia that are connected to energy metabolism and inflammatory responses.
Implications for Future Research
“Taken together, the results show that small vessel pathology can drive broader changes in the brain’s energy systems and immune responses,” explained Helena Karlström, senior lecturer and docent at the same department. “Understanding these mechanisms may help guide future research on potential treatments.”
The study’s insights into the relationship between CADASIL and brain function could pave the way for new therapeutic approaches. By addressing the underlying vascular issues and their impact on neuronal health, researchers aim to improve outcomes for those affected by this debilitating condition.
The findings from this research add a crucial layer of understanding to the complex interplay between genetics, vascular health, and cognitive function, particularly in hereditary diseases like CADASIL.
