New breakthrough approach to atherosclerosis and Alzheimer's disease

New breakthrough approach to atherosclerosis and Alzheimer's disease

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Alzheimer's and atherosclerosis are diseases associated with chronic inflammation in the brain and blood vessels. Proteins from the immune system keep this inflammation going. A fat metabolism protein body (ApoE), on the other hand, fights the inflammation and could be a role model in the future to stop it.

Approach to new therapies against atherosclerosis and Alzheimer's dementia

In cooperation with the Leibniz Institute for Natural Product Research and Infection Biology in Jena and other partners, researchers from the Ludwig Maximilian University of Munich (LMU) were able to show that the ApoE protein is a key molecule in the development of chronic inflammatory diseases and identified a promising one Approach to new therapies against atherosclerosis and Alzheimer's dementia. Her study results were published in the English journal "Nature Medicine".

ApoE as a key molecule and regulator

The researchers around Dr. According to Changjung Yin, Professor Andreas habenicht and Professor Christian Weber from the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases (IPEK) at the LMU Clinic, in cooperation with the Leibniz Institute for Natural Product Research and Infection Biology in Jena and other partners have now been able to demonstrate that ApoE acts as a key molecule and regulator in a central signaling cascade of the immune response and thus directly influences inflammation. ApoE is not only associated with atherosclerosis, but also with Alzheimer's disease, AIDS and many other inflammatory diseases.

New starting point for the development of further therapies

By treating them with an active ingredient that works on this cascade, the scientists succeeded in inhibiting atherosclerosis and inflammatory processes in the brain. The IPEK researchers have thus identified a completely unexpected but above all common function of ApoE in various diseases and found a starting point for the development of new therapies for these diseases.

ApoE has a positive effect on cardiovascular diseases

In humans, there are three different variants of ApoE, which have a broad spectrum of mechanisms of action, but whose different functions have so far remained unclear. It has been known since the early 1990s that carriers of the ApoE4 variant have a higher risk of developing a certain form of Alzheimer's disease. “This is why many Alzheimer's researchers consider ApoE to be harmful. However, ApoE apparently has a positive effect on cardiovascular diseases: mice that cannot produce this protein because the corresponding gene has been switched off show increased blood lipid levels and severe atherosclerosis, ”says Yin.

How does ApoE deficiency affect the brain?

Alzheimer's disease is known to be linked to inflammatory processes in the brain. To characterize the function of the protein more precisely, the researchers investigated, among other things, how ApoE deficiency affects the brain. In an important structure in the brain of patients - the so-called choroid plexus - they found pathological fat deposits in the majority of the affected subjects and little or no deposits in healthy patients. The choroid plexus is a central vein network in the brain, which is responsible for the formation of the blood-brain barrier and the brain metabolism as well as for the immigration of immune cells into the brain and therefore 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 develop dementia."

Fat deposits trigger inflammatory processes

As the researchers were able to show, the fat deposits trigger inflammatory processes by activating the so-called complement system, a signaling cascade of the immune system in which almost 30 proteins are involved. All human apo variants were able to mitigate this activation by binding to a particular protein in this system called C1q. ApoE was identified as a binding partner of C1q and as a direct and central regulator of this signal cascade. C1q normally initiates the activation of the classic complement system. “We have detected the resulting C1q-ApoE complex in locations as diverse as the choroid plexus, the Alzheimer's typical plaques in the brain and in atherosclerotic arteries of the heart, the arteries that supply the brain with blood and the main artery (aorta). The number of complexes correlated with the degree of dementia in Alzheimer's patients and with the severity of atherosclerosis, ”said Yin in a press release from the LMU.

Further therapeutic approaches with ApoE

In addition to the classic, there are two other activation methods for the complement system that do not require C1q. When looking for new active substances to reduce the fatal inflammatory reactions, the scientists therefore did not choose C1q directly as a possible target structure, but rather a specific factor that is a central component of all three activation pathways. “In fact, we managed to inhibit this factor using a so-called small interfering RNA, or siRNA for short,” says Yin. “In this way, we were able to greatly reduce inflammatory reactions in the brain and also atherosclerosis in mice. It could be that we were able to use it to uncover a long-sought common mechanism of action of ApoE in different and previously difficult to treat inflammatory diseases, ”the expert concluded. (fm)

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