A new study published in Brain shows that damage to small blood vessels in the hereditary disease CADASIL may disrupt important brain functions in the hippocampus, a region involved in memory. The findings help explain why many people with CADASIL develop cognitive problems and dementia.
CADASIL is caused by genetic variants in the NOTCH3 gene, which lead to degeneration of vascular smooth muscle cells and reduced blood flow in the brain. While the disease is known to cause strokes and white matter changes, less has been understood about how these vascular problems affect brain cells at the molecular level.
In the new study, researchers at Karolinska Institutet used several approaches, including a humanised mouse model carrying a CADASIL‑related gene variant, post‑mortem human brain tissue, and human vascular smooth muscle cells. They investigated how neuronal activity, mitochondria and the neurovascular unit were affected.
The team found that mice with CADASIL showed impaired gamma oscillations in the hippocampus-brain rhythms important for memory and learning. The mice also had shorter neuronal fibres and abnormal neuron shapes, observations that were mirrored in human CADASIL brain tissue.
"We saw clear changes in both neuronal structure and function," says Wenchao Shao , 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 recognised before."
The researchers also discovered lower levels of mitochondrial respiratory complexes in mouse hippocampus, brain vessels and human vascular cells. These human cells showed reduced oxygen consumption and ATP production, as well as a decline in glycolytic capacity. At the same time, they expressed more pro‑inflammatory genes.
In the mouse model, the hippocampal blood vessels accumulated the NOTCH3 extracellular domain and showed a loss of vascular smooth muscle cells and reduced vessel density. Imaging also revealed increased microglial attachment to vessels and a specialised microglial subgroup linked to energy metabolism and inflammation.
"Taken together, the results show that small vessel pathology can drive broader changes in the brain's energy systems and immune responses," says Helena Karlström , senior lecturer and docent at the same department . "Understanding these mechanisms may help guide future research on potential treatments."
Publication
Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL.
Shao W, Oliveira DV, Naia L, Li Y, Dahl Bjørnholm K, Isla AG, Uhlén P, Kalaria R, Lesnik Oberstein SAJ, Lendahl U, EnriqueArroyo-García L, Jin S, Karlström H
Brain 2026 Feb;():
