by Lund University

Altered NOTCH3 expression in leptomeningeal arteries of human acute TBI subjects. NOTCH3 expression in the leptomeningeal arteries of a, b control subjects and c–g brain samples surgically resected from severe, acute human TBI patients. a Representative bright-field images of NOTCH3 in leptomeningeal arteries of different sizes in control subjects. b The boxed area in a showing NOTCH3 staining through the full thickness of tunica media of artery walls of the control subject. c–g Transverse and longitudinal views of leptomeningeal arteries of acute human TBI patients showing a partial circumference abnormality of NOTCH3 expression in the tunica media (asterisks in c, e, and arrows in f). Scale bars = 200 μm in (a), 20 μm in (b–g). Credit: Acta Neuropathologica (2025). DOI: 10.1007/s00401-025-02848-9

A study at Lund University reveals that traumatic brain injury alters the small vessels in the brain, resulting in an accumulation of amyloid beta—a hallmark of Alzheimer's disease. The findings suggest that vascular dysfunction could be an early driver in neurodegenerative disorders rather than being caused by neuronal damage. The study is published in Acta Neuropathologica.

An increased risk of dementia among individuals exposed to brain trauma, traumatic brain injury, has been known for almost a century. Still, we know very little about the molecular causes behind this, which makes it difficult to find effective treatments to prevent dementia development among those affected with traumatic brain injury. However, a research team at the strategic research area MultiPark, Lund University argues that the blood vessels in the brain hold the keys to future therapies.

Brain trauma usually impairs cerebral blood flow, possibly through pathological changes in the vascular smooth muscle cells in the vascular wall. These blood flow impairments can lead to secondary brain injuries, worsening the damage to the brain, although it remains unknown exactly how this occurs.

To bridge this gap, Niklas Marklund, professor at Lund University and neurosurgical consultant at Skåne University hospital, decided to take a deeper look into the molecular details together with the experimental scientist Ilknur Özen. In collaboration with Uppsala University, they investigated brain tissue from 15 patients, surgically removed due to bleeding and swelling within a week following their traumatic brain injuries. They found that the changes in the vascular smooth muscle cells coincided with increased aggregation of amyloid-beta, a protein linked to Alzheimer's disease.

"We were surprised to see that even young patients displayed this accumulation of amyloid beta together with the vascular alterations caused by the brain trauma," says Özen, first author of the study. She continues: "Our findings suggest that vascular changes may be more important for neurodegeneration than previously thought."

Marklund adds, "This challenges the existing paradigm in neurodegeneration-related diseases by indicating that vascular dysfunction could be an early event that triggers the progression of amyloid-related diseases rather than being caused by neuronal damage."

While aging leads to functional changes in the vasculature, brain trauma may exacerbate and accelerate these processes even in younger patients. Still, far from everybody affected by brain trauma develops Alzheimer's disease. That is why more research is needed.

"We are not there yet, but hopefully, increased knowledge about what happens at a molecular level in the blood vessel cells following brain trauma will open up possibilities for novel treatments," concludes Marklund.

More information: Ilknur Özen et al, Traumatic brain injury causes early aggregation of beta-amyloid peptides and NOTCH3 reduction in vascular smooth muscle cells of leptomeningeal arteries, Acta Neuropathologica (2025). DOI: 10.1007/s00401-025-02848-9

Provided by Lund University