Medin Promotes Amyloid-ß Aggregation in Alzheimer’s

Researchers at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) have found that the amyloid protein medin is deposited in the blood vessels of the brains of Alzheimer's patients, along with the protein amyloid-β. The findings point to medin as a potential target for preventing or treating Alzheimer’s.

Amyloid-β is best known amyloid because it clumps together in the brains of Alzheimer's patients. But aggregates of both amyloid-β and medin are deposited as plaques directly in the brain tissue and also in its blood vessels, damaging both nerve cells and the blood vessels, respectively. Although many studies have focused on amyloid-β, medin has not been a focus of interest. 

"Medin has been known for over 20 years, but its influence on diseases was previously underestimated. We were able to show that pathological changes in the blood vessels of Alzheimer's patients are significantly enhanced by medin," says study lead Dr. Jonas Neher from the Tübingen site of DZNE.

Medin is found in the blood vessels of almost everybody over 50 years of age, making it the most common amyloid known. Neher and colleagues previously reported in the journal PNAS that medin develops in aging mice, and the older the mice get, the more medin accumulates in the blood vessels of their brains. They also found that, when the brain becomes active and triggers an increase in blood supply, vessels with medin deposits expand more slowly than those without medin. This ability of blood vessels to expand, however, is important to optimally supply the brain with oxygen and nutrients.

The more recent study, published in the journal Nature, built on this work specifically in the context of Alzheimer's disease. The DZNE team stained tissue sections from both Alzheimer's mouse models and Alzheimer's patients in such a way that specific proteins become visible. This allowed them to show that medin and amyloid-β are deposited together in blood vessels of the brain. In a next step, they were able to prove that these two amyloids also co-aggregate and form mixed deposits. "Amazingly, medin interacts directly with amyloid-β and promotes its aggregation—this was completely unknown," Neher adds.

The authors were able to show in the mouse model that medin accumulates even more strongly in the brain’s blood vessels if amyloid-β deposits are also present. Importantly, these findings were confirmed when brain tissue from organ donors with Alzheimer's dementia was analyzed. However, when mice were genetically modified to prevent medin formation, significantly fewer amyloid-β deposits developed, and as a result, less damage to blood vessels occurred.

The findings suggest medin could be a therapeutic target to prevent vascular damage and cognitive decline resulting from amyloid accumulation in the blood vessels of the brain. It is known that, in addition to amyloid-β aggregates in brain tissue, the development of Alzheimer’s disease is also promoted by vascular alterations that reduce function or damage to blood vessels. Therefore, treatments that target not only plaques but also affected blood vessels could help patients.

In a next step, it will be necessary to determine if medin aggregates can be removed therapeutically and whether this intervention actually has an effect on cognitive performance. The scientists first want to test this in mouse models, because these reflect the pathological changes in Alzheimer's patients very well.