Alzheimer’s disease is a progressive brain disorder that affects memory, thinking and behavior. It is the most common cause of dementia in older adults and is characterized by the loss of brain cells and shrinkage of brain tissue. According to the World Health Organization, Alzheimer’s disease affects approximately 50 million people worldwide and this number is expected to triple by 2050.
Researchers at the German Center for Neurodegenerative Diseases (DZNE) have discovered that the protein Medin aggregates together with amyloid-β in the blood vessels of the brain
Alzheimer
Alzheimer’s disease is a disease that attacks the brain, causing a decline in mental ability that worsens over time. It is the most common form of dementia, accounting for 60 to 80 percent of dementia cases. There is currently no cure for Alzheimer’s disease, but there are medications that can help relieve symptoms.
” data-gt-translate-attributes=”[“attribute”:”data-cmtooltip”, “format”:”html”]”>Alzheimer’s patients. Their results were recently published in the renowned scientific journal Nature.
“Medin has been known for over 20 years, but its impact on disease has been underestimated. We were able to show that Medin significantly intensifies pathological changes in the blood vessels of Alzheimer’s patients,” says Dr. Jonas Neher from the Tübingen site of the DZNE, who led the study.
The Hertie Institute for Clinical Brain Research in Tübingen, the University of Tübingen and various international institutions and partners were also involved in this long-term project.
Medin belongs to the group of amyloids. Of these proteins, amyloid-β is best known for clumping together in the brains of Alzheimer’s patients. These aggregates are then deposited as so-called plaques directly in the brain tissue, but also in its blood vessels, thereby damaging the nerve cells and blood vessels. But while many studies have focused on amyloid-β, Medin has not been the focus of attention. “There was little evidence of a pathology, i.e. a clinically conspicuous finding in connection with Medin – and that is often the prerequisite for a more detailed examination of an amyloid,” explains Jonas Neher.
However, Medin is actually found in the blood vessels of almost everyone over the age of 50, making it the most common amyloid known. Jonas Neher and his team originally discovered that Medin even develops in aging mice and reported on this discovery two years ago in the scientific journal PNAS. The older the mice get, the more Medin accumulates in the blood vessels of their brain, according to the findings at the time. In addition, when the brain becomes active and triggers an increase in blood flow, vessels with Medin deposits dilate more slowly than those without Medin. However, this ability of the blood vessels to expand is important in order to optimally supply the brain with oxygen and nutrients.
For their latest findings, the researchers built on this foundation and looked specifically at Alzheimer’s disease. First, they were able to show in Alzheimer’s mouse models that Medin accumulates even more in the blood vessels of the brain if amyloid-β deposits are also present. Importantly, these results were confirmed when brain tissue from organ donors with Alzheimer’s dementia was analyzed. However, when mice were genetically engineered to prevent the formation of Medin, significantly fewer amyloid-β deposits formed and, as a result, less damage to blood vessels occurred.
“Only a handful of research groups worldwide are working on Medin,” says Jonas Neher. Recently, a study from the USA reported that Medin levels can increase in Alzheimer’s patients. However, it remained unclear whether this increase is merely a consequence of the disease or one of the causes.
“We have now been able to show in many experiments that Medin actually promotes vascular pathology in Alzheimer’s models,” says Neher. So Medin deposits are actually a cause of blood vessel damage. “And that suggests that Medin is one of the causes of the disease,” Neher said.
In their studies, the researchers stained tissue sections from both mice and Alzheimer’s patients in such a way that specific proteins become visible. They were thus able to show that Medin and amyloid-β are deposited together in the blood vessels of the brain – co-localization is the technical term for this. In the next step, they were able to prove that these two amyloids also accumulate, i.e. form mixed deposits.
“Amazingly, Medin interacts directly with amyloid-β and promotes its aggregation – that was completely unknown,” Jonas Neher summarizes the results.
It is precisely from this finding that the researchers draw hope for the development of a new therapy. “Medin might be a therapeutic target to prevent vascular damage and cognitive decline resulting from the accumulation of amyloid in the blood vessels of the brain,” they conclude. It is undisputed among experts that, in addition to amyloid-β aggregates in the brain tissue, vascular changes – i.e. reduced function or damage to blood vessels – also promote the development of Alzheimer’s disease. Therefore, treatments that target not only plaques but also affected blood vessels might help patients.
The next step is to clarify whether 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.
Reference: “Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease” by Jessica Wagner, Karoline Degenhardt, Marleen Veit, Nikolaos Louros, Katerina Konstantoulea, Angelos Skodras, Katleen Wild, Ping Liu, Ulrike Obermüller, Vikas Bansal, Anupriya Dalmia, Lisa M. Häsler, Marius Lambert, Matthias De Vleeschouwer, Hannah A. Davies, Jillian Madine, Deborah Kronenberg-Versteeg, Regina Feederle, Domenico Del Turco, K. Peter R. Nilsson, Tammaryn Lashley, Thomas Deller, Marla Gearing, Lary C Walker , Peter Heutink, Frederic Rousseau, Joost Schymkowitz, Mathias Jucker and Jonas J. Neher, November 16, 2022, Nature.
DOI: 10.1038/s41586-022-05440-3
