Anyone who has had to deal with inflammatory diseases knows how difficult it is to find suitable forms of therapy. However, healing treatments for atherosclerosis, Alzheimer’s dementia or AIDS are still not possible. That is why there is hope for research work.

Multifunctional protein

The scientists around Dr. Changjung Yin, Professor Andreas Habenicht and Professor Christian Weber from the Institute for Prophylaxis and Epidemiology of Circulatory Diseases (IPEK) at the LMU Clinic identified a promising approach for new therapies in cooperation with the Leibniz Institute for Natural Product Research and Infection Biology in Jena and other partners. They found out that the apolipoprotein E, ApoE for short, a multifunctional protein, plays a decisive role. It acts as a regulator of fat metabolism. Numerous other properties have also been described. The interesting thing is that the protein is associated with atherosclerosis, Alzheimer’s dementia and AIDS.

Direct influence on inflammations

The research work of the scientists showed that ApoE works as a key molecule and regulator. Thus, it interferes with a central signalling cascade of the immune ration. The result: it directly influences inflammations.

The scientists carried out a treatment with an active substance that starts at this cascade. This enabled them to inhibit atherosclerosis and inflammatory processes in the brain. In doing so, the researchers unexpectedly deciphered a common function of ApoE in various diseases. This could be a new starting point for developing new therapies for these diseases.

Broad spectrum

The research results are so interesting because until now the functions of ApoE were largely unknown. There are three different variants of the multifunctional protein as it acts in the human body. Since the early 1990s, it has been known that the variant ApoE4 is responsible for the development of a certain form of Alzheimer’s dementia. “Many Alzheimer researchers therefore regard ApoE as harmful. In terms of cardiovascular diseases, however, ApoE appears to have a positive effect: Mice that are unable to produce this protein because the corresponding gene has been switched off (“knocked out”) show elevated blood lipid levels and severe atherosclerosis,” says Yin.

Alzheimer’s dementia

It is also known that inflammatory processes in the brain are responsible for Alzheimer’s dementia. The researchers therefore investigated how ApoE deficiency affects the brain. In an important structure – the choroid plexus – they found pathological fat deposits in diseased patients and no or very little deposits in healthy patients.

The choroid plexus is a central vein plexus in the brain. It is responsible for the formation of the blood-brain barrier and the brain’s metabolism. It is also responsible for the immigration of immune cells into the brain. It is thus an important interface between the immune system, the cardiovascular system and the brain. “These fat deposits are a completely new clinical picture that was previously completely unknown,” says Yin. “The more pronounced these deposits are, the earlier and more pronounced the patients developed dementia.

Various processes due to fat deposition

The researchers have shown that fat deposits trigger inflammatory processes. They activate the so-called complement system. It is a signalling cascade of the immune system in which almost 30 proteins are involved. All Apo variants in the human body were able to weaken this activation by forming the C1q protein. The researchers thus identified ApoE as a binding partner of C1q, a direct and central regulator of this signalling cascade.

“We have detected the resulting C1q-ApoE complex in locations as diverse as the choroid plexus, Alzheimer’s plaques in the brain and in atherosclerotic arteries of the heart, the arteries that supply the brain with blood and the aorta. The number of complexes correlated with the degree of dementia in Alzheimer’s patients and with the severity of atherosclerosis,” explains Yin.

Further activation paths

However, there are two further activation paths for the complement system. They do not require C1q. However, the scientists did not choose this protein as a possible target structure. Rather, they chose a specific factor that is a central component of all three activation pathways.
“In fact, we succeeded in inhibiting this factor with the help of small interfering RNA, siRNA for short,” said Yin. “In this way, we were able to considerably reduce inflammatory reactions in the brain and also atherosclerosis in mice. We might have been able to uncover a long-awaited joint mechanism of action of ApoE in various inflammatory diseases that were previously difficult to treat.”
The scientific work will be continued in the DFG Collaborative Research Centre 1123 and in the SyNergy excellence cluster.

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