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Photo Credit: Liza Simonsson.
Scientific Frontline: Extended "At a Glance" Summary
The Core Concept: CADASIL is a hereditary condition caused by NOTCH3 gene variants that degenerate vascular smooth muscle cells, leading to strokes, white matter changes, and cognitive decline.
Key Distinction/Mechanism: Unlike general vascular descriptions, new research identifies a specific molecular cascade where small vessel pathology disrupts mitochondrial function and energy production in the hippocampus. This leads to impaired gamma oscillations—brain rhythms essential for memory—and triggers inflammatory immune responses via specialized microglia.
Major Frameworks/Components:
- Mitochondrial Dysfunction: Reduced respiratory complexes and ATP production in brain vessels and cells.
- Hippocampal Vulnerability: Structural changes to neurons and impaired gamma oscillations.
- Neurovascular Unit Disruption: Loss of vascular smooth muscle cells and accumulation of NOTCH3 proteins.
- Immune Response: Increased attachment of microglia to vessels, specifically a subgroup linked to metabolism and inflammation.
Branch of Science: Neurology, Vascular Biology, Neuroscience, and Genetics.
Future Application: These insights into energy failure and immune activation provide specific targets for developing new therapeutic interventions to halt cognitive decline in CADASIL patients.
Why It Matters: This research bridges the gap between vascular damage and actual memory loss, revealing that the disease attacks the brain’s energy systems and rhythm-generating mechanisms, not just its blood flow structure.
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 leads 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 humanized 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.
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| Wenchao Shao Photo Credit: Liza Simonsson |
“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 recognized 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.
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| Helena Karlström Photo Credit: Subash Malik |
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 specialized 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.”
Published in journal: Brain
Title: Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL
Authors: Wenchao Shao, Daniel V Oliveira, Luana Naia, Yue Li, Katrine Dahl Bjørnholm, Arturo G Isla, Per Uhlén, Raj Kalaria, Saskia A J Lesnik Oberstein, Urban Lendahl, Luis EnriqueArroyo-García, ShaoBo Jin, and Helena Karlström
Source/Credit: Karolinska Institutet
Reference Number: ns020426_02